Pyrrolotriazine compounds as TAM inhibitors

ABSTRACT

This application relates to compounds of Formula I:or pharmaceutically acceptable salts thereof, which are inhibitors of TAM kinases which are useful for the treatment of disorders such as cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/559,841, filed Sep. 4, 2019, which is a continuation of Ser. No.15/971,017, filed May 4, 2018, which is a continuation of U.S.application Ser. No. 15/469,975, filed Mar. 27, 2017 which claimspriority to U.S. Provisional Patent Application Nos. 62/314,066, filedon Mar. 28, 2016; 62/362,934, filed on Jul. 15, 2016; 62/438,750, filedon Dec. 23, 2016; the entireties of which are incorporated herein byreference.

TECHNICAL FIELD

This application relates to pyrrolotriazine inhibitors of TAM kinases,and in one embodiment inhibitors of AXL and MER kinases, which areuseful in the treatment of disorders such as cancer, as well aspharmaceutical compositions related thereto.

BACKGROUND OF INVENTION

Receptor tyrosine kinases (RTKs) are cell surface proteins that transmitsignals from the extracellular environment to the cell cytoplasm andnucleus to regulate cellular events such as survival, growth,proliferation, differentiation, adhesion and migration.

The TAM subfamily consists of three RTKs including Tyro3, AXL and Mer(Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al.,2008, Advances in Cancer Research 100, 35-83). TAM kinases arecharacterized by an extracellular ligand binding domain consisting oftwo immunoglobulin-like domains and two fibronectin type III domains.Two ligands, growth arrest specific 6 (GAS6) and protein S (PROS1), havebeen identified for TAM kinases. GAS6 can bind to and activate all threeTAM kinases, while PROS1 is a ligand for Mer and Tyro3 (Graham et al.,2014, Nature Reviews Cancer 14, 769-785).

AXL (also known as UFO, ARK, JTK11 and TYRO7) was originally identifiedas a transforming gene from DNA of patients with chronic myelogenousleukemia (O'Bryan et al., 1991, Mol Cell Biol 11, 5016-5031; Graham etal., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008,Advances in Cancer Research 100, 35-83). GAS6 binds to AXL and inducessubsequent auto-phosphorylation and activation of AXL tyrosine kinase.AXL activates several downstream signaling pathways including PI3K-Akt,Raf-MAPK, PLC-PKC (Feneyrolles et al., 2014, Molecular CancerTherapeutics 13, 2141-2148; Linger et al., 2008, Advances in CancerResearch 100, 35-83).

MER (also known as MERTK, EYK, RYK, RP38, NYK and TYRO12) was originallyidentified as a phospho-protein from a lymphoblastoid expression library(Graham et al., 1995, Oncogene 10, 2349-2359; Graham et al., 2014,Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances inCancer Research 100, 35-83). Both GAS6 and PROS1 can bind to Mer andinduce the phosphorylation and activation of Mer kinase (Lew et al.,2014). Like AXL, MER activation also conveys downstream signalingpathways including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Advancesin Cancer Research 100, 35-83).

TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, ETK2) was originallyidentified through a PCR-based cloning study (Lai et al., Neuron 6,691-70, 1991; Graham et al., 2014, Nature Reviews Cancer 14, 769-785;Linger et al., 2008, Advances in Cancer Research 100, 35-83). Bothligands, GAS6 and PROS1, can bind to and activate TYRO3. Although thesignaling pathways downstream of TYRO3 activation are the least studiedamong TAM RTKs, it appears that both PI3K-Akt and Raf-MAPK pathways areinvolved (Linger et al., 2008, Advances in Cancer Research 100, 35-83).AXL, MER and TYRO3 are found to be over-expressed in cancer cells.

Accordingly, there is a need for compounds and methods of use thereoffor the modulation of TAM kinases in the treatment of cancer.

SUMMARY OF INVENTION

In one aspect, the present application relates to compounds havingFormula I:

or a pharmaceutically acceptable salt thereof, wherein variables R¹, R²,R³, Cy^(C) and Cy^(B) are as described herein.

The present application further provides compositions comprising acompound described herein, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.

The present application also provides methods of inhibiting TAM kinases,and in one embodiment methods of inhibiting AXL and MER kinases,comprising contacting one or more TAM kinase with a compound describedherein, or a pharmaceutically acceptable salt thereof.

The present application also provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present application further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for manufactureof a medicament for use in any of the methods described herein.

DETAILED DESCRIPTION

The application provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is A¹-A²-A³-R^(A);

R² is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, cyano-C₁₋₃ alkyl or C₁₋₆ alkoxyalkyl;

R³ is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a), SR^(a),C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)S(O)₂R^(b) orS(O)₂R^(b); wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl are optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, CN, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)S(O)₂R^(b), S(O)₂R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)₂NR^(c)R^(d) and Cy^(R3);

A¹ is selected from a bond, Cy^(A1), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

A² is selected from a bond, Cy^(A2), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

A³ is selected from a bond, Cy^(A3), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

R^(A) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₃₋₆ cycloalkyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)OR^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),or S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl or C₁₋₆ haloalkyl isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹;

Y is O, S, S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), NR^(f)C(O)NR^(f),NR^(f)S(O)₂NR^(f), S(O)₂NR^(f), NR^(f)S(O)₂, or NR^(f);

each R^(f) is independently selected from H and C₁₋₃ alkyl;

Cy^(A1) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A1);

each R^(A1) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A2) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A2);

each R^(A2) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A3);

each R^(A3) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(R3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(g);

Cy^(C) is phenylene or 5-6 membered heteroarylene; wherein the 5-6membered heteroarylene has at least one ring-forming carbon atom and 1or 2 ring-forming heteroatoms independently selected from N, O, and S;and wherein the phenylene and 5-6 membered heteroarylene are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(C);

each R^(C) is independently selected from OH, CN, halo, C₁₋₄ alkyl, C₁₋₃haloalkyl, C₁₋₄ alkoxy, C₁₋₃ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, carbamyl, C₁₋₄ alkylcarbamyl, di(C₁₋₄alkyl)carbamyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄alkylaminosulfonyl, and di(C₁₋₄ alkyl)aminosulfonyl;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; andwherein the C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B); or

Cy^(B) is 6-10 membered aryl or 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein: (a) atleast one ring-forming carbon atom of the 5-10 membered heteroaryl issubstituted by oxo to form a carbonyl group; or (b) the 6-10 memberedaryl or 5-10 membered heteroaryl is substituted by halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); andwherein the 6-10 membered aryl or 5-10 membered heteroaryl is furtheroptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R¹¹ is independently selected from CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)OR^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)OR^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

R^(a) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(b) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(c) and R^(d) are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, phenyl-C₁₋₃alkylene, 5-6 membered heteroaryl-C₁₋₃ alkylene, and 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, phenyl-C₁₋₃ alkylene,5-6 membered heteroaryl-C₁₋₃ alkylene, and 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene are each optionally substituted with 1, 2or 3 substituents independently selected from R^(g);

R^(a1), R^(c1) and R^(d1) are each independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

R^(b1) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R^(e1) is selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²; or

alternatively, any R^(c2) and R^(d2) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,phenyl-C₁₋₄ alkylene, 5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7membered heterocycloalkyl-C₁₋₄alkylene; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R^(g); or

alternatively, any R^(c3) and R^(d3) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, any R^(c4) and R^(d4) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

provided that:

-   -   1) A³-A²-A³ is not Y—Y when one of A¹, A² or A³ is a bond, or        Y—Y—Y; and    -   2) when A³ is —Y— or —C₁₋₃ alkylene-Y— then R^(A) is H, C₁₋₆        alkyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl or C₁₋₆        haloalkyl is optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹.

In some embodiments, provided herein is a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is A¹-A²-A³-R^(A);

R² is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, cyano-C₁₋₃ alkyl or C₁₋₆ alkoxyalkyl;

R³ is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a), SR^(a),C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)S(O)₂R^(b) orS(O)₂R^(b); wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl are optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, CN, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)S(O)₂R^(b), S(O)₂R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)₂NR^(c)R^(d) and Cy^(R3);

A¹ is selected from a bond, Cy^(A1), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

A² is selected from a bond, Cy^(A2), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

A³ is selected from a bond, Cy^(A3), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

R^(A) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)OR^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl or C₁₋₆ haloalkyl is optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹¹;

Y is O, S, S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), NR^(f)C(O)NR^(f),NR^(f)S(O)₂NR^(f), S(O)₂NR^(f), NR^(f)S(O)₂, or NR^(f);

each R^(f) is independently selected from H and C₁₋₃ alkyl;

Cy^(A1) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A1);

each R^(A1) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A2) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A2);

each R^(A2) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A3);

each R^(A3) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(R3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(g);

Cy^(C) is phenylene or 5-6 membered heteroarylene; wherein the 5-6membered heteroarylene has at least one ring-forming carbon atom and 1or 2 ring-forming heteroatoms independently selected from N, O, and S;and wherein the phenylene and 5-6 membered heteroarylene are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(C);

each R^(C) is independently selected from OH, CN, halo, C₁₋₄ alkyl, C₁₋₃haloalkyl, C₁₋₄ alkoxy, C₁₋₃ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, carbamyl, C₁₋₄ alkylcarbamyl, di(C₁₋₄alkyl)carbamyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄alkylaminosulfonyl, and di(C₁₋₄ alkyl)aminosulfonyl;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; andwherein the C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B); or

Cy^(B) is 6-10 membered aryl or 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein: (a) atleast one ring-forming carbon atom of the 5-10 membered heteroaryl issubstituted by oxo to form a carbonyl group; or (b) the 6-10 memberedaryl or 5-10 membered heteroaryl is substituted by halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); andwherein the 6-10 membered aryl or 5-10 membered heteroaryl is furtheroptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹¹ is independently selected from CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)OR^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)OR^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

R^(a) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(b) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(c) and R^(d) are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, phenyl-C₁₋₃alkylene, 5-6 membered heteroaryl-C₁₋₃ alkylene, and 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, phenyl-C₁₋₃ alkylene,5-6 membered heteroaryl-C₁₋₃ alkylene, and 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene are each optionally substituted with 1, 2or 3 substituents independently selected from R^(g);

R^(a1), R^(c1) and R^(d1) are each independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

R^(b1) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R^(e1) is selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²; or

alternatively, any R^(c2) and R^(d2) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,phenyl-C₁₋₄ alkylene, 5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7membered heterocycloalkyl-C₁₋₄ alkylene; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R^(g); or

alternatively, any R^(c3) and R^(d3) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, any R^(c4) and R^(d4) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

provided that:

-   -   1) A³-A²-A³ is not Y—Y when one of A¹, A² or A³ is a bond, or        Y—Y—Y; and    -   2) when A³ is —Y— or —C₁₋₃ alkylene-Y— then R^(A) is H, C₁₋₆        alkyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl or C₁₋₆        haloalkyl is optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹.

In some embodiments, A¹ is a bond.

In some embodiments, A² is a bond.

In some embodiments, A³ is a bond.

In some embodiments, R^(A) is H, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In some embodiments, R^(A) is C₁₋₆ alkyl.

In some embodiments, R^(A) is methyl or ethyl.

In some embodiments, A¹ is a bond. For example, R¹ is A²-A³-R^(A).

In some embodiments, A¹ is a bond, A² is a bond, and A³ is Cy^(A3). Forexample, R¹ is Cy^(A3)-R^(A).

In some embodiments, one of A¹, A², and A³ is not a bond.

In some embodiments, one of A¹, A², and A³ is —C₁₋₃ alkylene-, —Y—,—C₁₋₃ alkylene-Y—, or —Y—C₁₋₃ alkylene-. In some embodiments, one of A¹,A², and A³ is —C₁₋₆ alkylene- or —Y—. In some embodiments, one of A¹,A², and A³ is —C₁₋₆ alkylene-. In some embodiments, one of A¹, A², andA³ is methylene.

In some embodiments, R¹ is H, halo, C₁₋₆ alkyl or C₁₋₆ haloalkyl.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ is methylor ethyl.

In some embodiments, R¹ is A²-A³-R^(A).

In some embodiments, R¹ is Cy^(A3)-R^(A).

In some embodiments, Cy^(A3) is C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, or 4-7 membered heterocycloalkyl; each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(A3).

In some embodiments, Cy^(A3) is C₃₋₆ cycloalkyl or 4-6 memberedheterocycloalkyl, each optionally substituted with 1 or 2 substituentsindependently selected from R^(A3).

In some embodiments, Cy^(A3) is piperidinyl, cyclohexyl, ortetrahydropyranyl; each optionally substituted with 1 or 2 substituentsindependently selected from R^(A3).

In some embodiments, Cy^(A3) is C₃₋₆ cycloalkyl optionally substitutedwith 1, 2, 3 or 4 independently selected R^(A3) groups. In someembodiments, Cy^(A3) is cyclohexyl and cyclopropyl optionallysubstituted with 1, 2, 3 or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is 4-6 membered heterocycloalkyl optionallysubstituted with 1, 2, 3 or 4 independently selected R^(A3) groups. Insome embodiments, Cy^(A3) is piperidinyl or morpholinyl optionallysubstituted with 1, 2, 3 or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is 5-10 membered heteroaryl optionallysubstituted with 1, 2, 3 or 4 independently selected R^(A3) groups. Insome embodiments, Cy^(A3) is pyridyl optionally substituted with 1, 2, 3or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is piperidinyl, cyclohexyl,tetrahydropyranyl, pyrazolyl, pyridinyl, azetidinyl, cyclopropyl, ormorpholinyl; each optionally substituted with 1 or 2 substituentsindependently selected from R^(A3).

In some embodiments, Cy^(A3) is piperidinyl, pyridyl, morpholinyl,cyclohexyl, or tetrahydropyranyl; each optionally substituted with 1, 2,3 or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is piperidinyl optionally substituted with1, 2, 3 or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is cyclohexyl optionally substituted with1, 2, 3 or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is morpholinyl optionally substituted with1, 2, 3 or 4 independently selected R^(A3) groups.

In some embodiments, Cy^(A3) is

wherein Cy^(A3)-1, Cy^(A3)-2 and Cy^(A3)-3 are each optionallysubstituted with 1, 2 or 3 substituents independently selected fromR^(A3).

In some embodiments, A¹ is a bond, A² is a bond, A³ is a bond, and R^(A)is methyl or ethyl; or A¹ is a bond, A² is a bond, and A³ isCy^(A3)-R^(A) selected from

In some embodiments, R^(A) is C₁₋₆ alkyl, CN, OR^(a1), NR^(c1)R^(d1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) or S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl is optionally substituted with 1 or 2 substituents independentlyselected from R¹¹, provided that if R^(A) is attached to a nitrogenatom, then R^(A) is not CN, OR^(a1), or NR^(c1)R^(d1).

In some embodiments, R^(A) is C₁₋₆ alkyl, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), and S(O)₂R^(b1); wherein said C₁₋₆ alkylis optionally substituted with 1 substituent selected from R¹¹, providedthat if R^(A) is attached to a nitrogen atom, then R^(A) is not CN orOR^(a1). In some embodiments, R^(b1) is isopropyl.

In some embodiments, each R^(A) is independently selected from C₁₋₃alkyl, CN, OH, methylcarbonyl, methoxycarbonyl,N,N-dimethylaminocarbonyl, and methylsulfonyl, wherein said C₁₋₃ alkylis optionally substituted with a OH or OCH₃ group, provided that ifR^(A) is attached to a nitrogen atom, then R^(A) is not CN or OH.

In some embodiments, each R^(A) is independently selected from CH₃,CH₂CH₃, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃, C(O)CH₂OH, C(O)CH(OH)CH₃,S(O)₂CH₃, C(O)OCH₃, C(O)N(CH₃)₂, C(O)NHCH₃, C(O)N(CH₂CH₃)₂, andC(O)N(CH₃)(CH₂CH₃).

In some embodiments, each R^(A) is independently selected from CH₃,CH₂CH₃, CH(CH₃)₂, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃, C(O)CH₂CH₃,C(O)CH(CH₃)₂, C(O)CH₂OH, C(O)CH(OH)CH₃, S(O)₂CH₃, C(O)OCH₃, C(O)N(CH₃)₂,C(O)N(CH₂CH₃)₂, C(O)N(CH₃)(CH₂CH₃), C(O)NHCH₃, C(O)NH(CH₂CH₃) andC(O)[morpholin-4-yl].

In some embodiments, each R¹¹ is independently OR^(a3).

In some embodiments, each R¹¹ is independently OH or OCH₃.

In some embodiments, Cy^(A3) is piperidinyl, cyclohexyl,tetrahydropyranyl, pyrazolyl, pyridinyl, azetidinyl, cyclopropyl, ormorpholinyl; each optionally substituted with R^(A) independentlyselected from CH₃, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃, C(O)CH₂CH₃,C(O)CH(CH₃)₂, C(O)CH₂OH, C(O)CH(CH₃)OH, S(O)₂CH₃, C(O)OCH₃, C(O)N(CH₃)₂,C(O)NH(CH₃), C(O)N(CH₂CH₃)₂, C(O)NH(CH₂CH₃), C(O)N(CH₃)(CH₂CH₃),CH₂C(O)N(CH₃)₂, 1-methyl-2-oxopyrrolidin-3-yl, C(O)(cyclopropyl),N(CH₃)₂, and C(O)(morpholin-4-yl).

In some embodiments, Cy^(A3) is piperidinyl, cyclohexyl, ortetrahydropyranyl; each optionally substituted with R^(A) independentlyselected from CH₃, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃, C(O)CH₂OH,C(O)CH(CH₃)OH, S(O)₂CH₃, C(O)OCH₃, C(O)N(CH₃)₂, C(O)NH(CH₃),C(O)N(CH₂CH₃)₂, C(O)NH(CH₂CH₃) and C(O)N(CH₃)(CH₂CH₃).

In some embodiments, Cy^(A3) is piperidinyl, cyclohexyl, ortetrahydropyranyl; each optionally substituted with R^(A) independentlyselected from CH₃, CH₂CH₃, CH(CH₃)₂, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃,C(O)CH₃, C(O)CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂OH, C(O)CH(OH)CH₃, S(O)₂CH₃,C(O)OCH₃, C(O)N(CH₃)₂, C(O)N(CH₂CH₃)₂, C(O)N(CH₃)(CH₂CH₃), C(O)NHCH₃,C(O)NH(CH₂CH₃) and C(O)(morpholin-4-yl)

In some embodiments, Cy^(A3) is piperidinyl, pyridyl, morpholinyl,cyclohexyl, or tetrahydropyranyl; each optionally substituted with 1, 2,3 or 4 groups independently selected from CH₃, CH₂CH₃, CN, OH, CH₂CH₂OH,CH₂CH₂OCH₃, C(O)CH₃, C(O)CH₂OH, C(O)CH(OH)CH₃, S(O)₂CH₃, C(O)OCH₃,C(O)N(CH₃)₂, C(O)NHCH₃, C(O)N(CH₂CH₃)₂, and C(O)N(CH₃)(CH₂CH₃).

In some embodiments, A¹ is a bond, A² is Cy^(A2), A³ is —Y—, R^(A) isC₃₋₆ cycloalkyl (e.g., cyclopropyl), —Y— is C(O), and Cy^(A2) is 4-7membered heterocycloalkyl (e.g., piperidinyl).

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R² is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, or C₁₋₄ haloalkoxy. In some embodiments, R² is H or C₁₋₄ alkyl.In some embodiments, R² is H.

In some embodiments, R³ is H.

In preferred embodiments, Cy^(B) forms a hydrogen bond with the NH ofthe amide group. For example, if the Cy^(B) group has an oxo group, theCy^(B) can form a hydrogen bond through the carbonyl group with the NHof the amide group. Similarly, Cy^(B) can be substituted with anelectron donating substituent capable of forming a hydrogen bond withthe NH of the amide group. Below are illustrative examples wherein W isan electron donating group such as halo, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2):

In some embodiments, Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 memberedheterocycloalkyl; wherein at least one ring-forming carbon atom of C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo toform a carbonyl group; wherein the 4-10 membered heterocycloalkyl has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; and wherein the C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3or 4 substituents independently selected from R^(B); or Cy^(B) is 5-10membered heteroaryl; wherein the 5-10 membered heteroaryl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein: (a) at least one ring-forming carbon atomof the 5-10 membered heteroaryl is substituted by oxo to form a carbonylgroup; or (b) the 5-10 membered heteroaryl is substituted by halo, CN,NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); andwherein the 5-10 membered heteroaryl is further optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R^(B).

In some embodiments, Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 memberedheterocycloalkyl; wherein at least one ring-forming carbon atom of C₃₋₁₀cycloalkyl and 4-10 membered heterocycloalkyl is substituted by oxo toform a carbonyl group; wherein the 4-10 membered heterocycloalkyl has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; and wherein the C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3or 4 substituents independently selected from R^(B).

In some embodiments, Cy^(B) is 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein: (a) atleast one ring-forming carbon atom of the 5-10 membered heteroaryl issubstituted by oxo to form a carbonyl group; or (b) the 5-10 memberedheteroaryl is substituted by halo, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); and wherein the5-10 membered heteroaryl is further optionally substituted with 1, 2, 3or 4 substituents independently selected from R^(B).

In some embodiments, Cy^(B) is 4-10 membered heterocycloalkyl; whereinat least one ring-forming carbon atom of 4-10 membered heterocycloalkylis substituted by oxo to form a carbonyl group; wherein the 4-10membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; and wherein the 4-10 membered heterocycloalkyl is optionallysubstituted with 1, 2 or 3 substituents independently selected fromR^(B); or

Cy^(B) is 5-6 membered heteroaryl, having at least one ring-formingcarbon atom which is substituted by oxo to form a carbonyl group and 1or 2 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-6 memberedheteroaryl is further optionally substituted with 1, 2, or 3substituents independently selected from R^(B).

In some embodiments, Cy^(B) is 4-10 membered heterocycloalkyl; whereinat least one ring-forming carbon atom of 4-10 membered heterocycloalkylis substituted by oxo to form a carbonyl group; wherein the 4-10membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; and wherein the 4-10 membered heterocycloalkyl is optionallysubstituted with 1, 2 or 3 substituents independently selected fromR^(B).

In some embodiments, Cy^(B) is 5-10 membered heteroaryl, having at leastone ring-forming carbon atom which is substituted by oxo to form acarbonyl group and 1 or 2 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein the 5-6 membered heteroaryl is further optionally substitutedwith 1, 2, or 3 substituents independently selected from R^(B).

In some embodiments, Cy^(B) is 4-10 membered heterocycloalkyl or 5-10membered heteroaryl wherein one ring-forming carbon atom at the orthoposition is substituted by oxo to form a carbonyl group. The orthoposition refers to the ring-forming carbon atom directly adjacent to thering-forming atom connecting the Cy^(B) group to the—C(═O)NH—Cy^(C)-linker.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, Cy^(B)-3, Cy^(B)-4, Cy^(B)-5, Cy^(B)-6, andCy^(B)-7 are each optionally substituted with 1, 2 or 3 independentlyselected R^(B) groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-8, Cy^(B)-9, Cy^(B)-10, Cy^(B)-4, and Cy^(B)-11 are eachoptionally substituted with 1, 2 or 3 independently selected R^(B)groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, Cy^(B)-3, Cy^(B)-8, Cy^(B)-9, Cy^(B)-10,Cy^(B)-4, and Cy^(B)-11 are each optionally substituted with 1, 2 or 3independently selected R^(B) groups.

In some embodiments, Cy^(B) is Cy^(B)-1 optionally substituted with 1, 2or 3 independently selected R^(B) groups. In some embodiments, Cy^(B) isCy^(B)-2 optionally substituted with 1, 2 or 3 independently selectedR^(B) groups. In some embodiments, Cy^(B) is Cy^(B)-3 optionallysubstituted with 1, 2 or 3 independently selected R^(B) groups. In someembodiments, Cy^(B) is Cy^(B)-4 optionally substituted with 1, 2 or 3independently selected R^(B) groups. In some embodiments, Cy^(B) isCy^(B)-5 optionally substituted with 1, 2 or 3 independently selectedR^(B) groups. In some embodiments, Cy^(B) is Cy^(B)-6 optionallysubstituted with 1, 2 or 3 independently selected R^(B) groups. In someembodiments, Cy^(B) is Cy^(B)-7 optionally substituted with 1, 2 or 3independently selected R^(B) groups.

In some embodiments, Cy^(B) is

In some embodiments, Cy^(B) is Cy^(B)-1a. In some embodiments, Cy^(B) isCy^(B)-2a. In some embodiments, Cy^(B) is Cy^(B)-3a. In someembodiments, Cy^(B) is Cy^(B)-4a. In some embodiments, Cy^(B) isCy^(B)-5a. In some embodiments, Cy^(B) is Cy^(B)-6a. In someembodiments, Cy^(B) is Cy^(B)-7a.

In some embodiments, Cy^(B) is C₃₋₁₀ cycloalkyl optionally substitutedwith 1, 2 or 3 independently selected R^(B) groups. In some embodiments,Cy^(B) is cyclopropyl.

In some embodiments, Cy^(B) is cyclopropyl,

wherein the cyclopropyl, Cy^(B)-1 and Cy^(B)-2 are each optionallysubstituted with 1, 2 or 3 independently selected R^(B) groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, Cy^(B)-3, and Cy^(B)-10 are each optionallysubstituted with 1, 2 or 3 substituents independently selected fromR^(B).

In some embodiments, Cy^(B) is

wherein Cy^(B)-1 and Cy^(B)-2 are each optionally substituted with 1, 2or 3 independently selected R^(B) groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, Cy^(B)-3, Cy^(B)-4 and Cy^(B)-5 are eachoptionally substituted with 1, 2 or 3 independently selected R^(B)groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1 and Cy^(B)-2 are each optionally substituted with 1, 2or 3 substituents independently selected from R^(B).

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2 and Cy^(B)-3 are each optionally substitutedwith 1, 2 or 3 independently selected R^(B) groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1 is optionally substituted with 1, 2 or 3 independentlyselected R^(B) groups. In some embodiments, Cy^(B) is

wherein Cy^(B)-2 is optionally substituted with 1, 2 or 3 independentlyselected R^(B) groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-3 is optionally substituted with 1, 2 or 3 independentlyselected R^(B) groups.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1 and Cy^(B)-2 are each optionally substituted with 1, 2or 3 substituents independently selected from R^(B);

each R^(B) is independently methyl, ethyl, isopropyl, sec-butyl, orphenyl, each of which is optionally substituted by 1 or 2 substituentsindependently selected from R¹²;

each R¹² is independently selected from halo, phenyl, and OR^(a4);wherein said phenyl is optionally substituted by 1 or 2 substituentsindependently selected from R^(g) group;

each R^(a4) is H or C₁₋₃ alkyl; and

each R^(g) is independently selected from halo.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, Cy^(B)-3, and Cy^(B)-10 are each optionallysubstituted with 1, 2 or 3 substituents independently selected fromR^(B);

each R^(B) is independently methyl, ethyl, isopropyl, sec-butyl,2-pyridinyl, or phenyl, each of which is optionally substituted by 1 or2 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, halo, phenyl, andOR^(a4); wherein said C₁₋₆ alkyl and phenyl are each optionallysubstituted by 1 or 2 substituents independently selected from R^(g)group;

each R^(a4) is H or C₁₋₃ alkyl; and

each R^(g) is independently selected from halo.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2 and Cy^(B)-3 are each optionally substitutedwith 1, 2 or 3 substituents independently selected from R^(B);

each R^(B) is independently methyl, ethyl, isopropyl, sec-butyl, orphenyl, each of which is optionally substituted by 1 or 2 substituentsindependently selected from R¹²;

each R¹² is independently selected from halo, phenyl, and OR^(a4);wherein said phenyl is optionally substituted by 1 or 2 substituentsindependently selected from R^(g) group;

each R^(a4) is H or C₁₋₃ alkyl; and

each R^(g) is independently selected from halo.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1 and Cy^(B)-2 are each optionally substituted with 1, 2or 3 groups independently selected from unsubstituted phenyl,4-fluoro-phenyl, CH₂(phenyl), CH(CH₂OH)phenyl, CH₃, CH₂CH₃,CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃, CH₂CH₂OH, OCH₂CH₃ and OCH₃.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, and Cy^(B)-3 are each optionally substitutedwith 1, 2 or 3 groups independently selected from unsubstituted phenyl,4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-pyridinyl,CH₂(phenyl), CH(CH₂OH)phenyl, CH₃, CH₂CH₃, CH(CH₃)₂, CH(CH₂OH)CH₂CH₃,CH(CH₂OH)CH₃, CH₂CH₂OH, OCH₂CH₃ and OCH₃

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2 and Cy^(B)-3 are each optionally substitutedwith 1, 2 or 3 substituents independently selected from unsubstitutedphenyl, 4-fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, CH₂(phenyl),CH(CH₂OH)phenyl, CH₃, CH₂CH₃, CH(CH₃)₂, CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃,CH₂CH₂OH, OCH₂CH₃ and OCH₃.

In some embodiments, Cy^(B) is

wherein Cy^(B)-2 and Cy^(B)-3 are each optionally substituted 1, 2 or 3groups independently selected from unsubstituted phenyl, CH(CH₃)₂, and2-pyridinyl.

In some embodiments, Cy^(B) is

wherein Cy^(B)-2 is optionally substituted 1, 2 or 3 groupsindependently selected from unsubstituted phenyl, CH(CH₃)₂, and2-pyridinyl.

In some embodiments, Cy^(B) is

wherein Cy^(B)-3 is optionally substituted 1, 2 or 3 groupsindependently selected from unsubstituted phenyl, CH(CH₃)₂, and2-pyridinyl.

In some embodiments, Cy^(B) is

wherein Cy^(B)-3 is substituted with unsubstituted phenyl and CH(CH₃)₂.

In some embodiments, Cy^(B) is

wherein Cy^(B)-3 is substituted with pyridinyl (e.g., 2-pyridinyl,3-pyridinyl, and 4-pyridinyl) and CH(CH₃)₂.

In some embodiments, each R^(B) is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), and NR^(c2)C(O)OR^(a2); wherein said C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹².

In some embodiments, each R^(B) is independently unsubstituted phenyl,4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, CH₂(phenyl),CH(CH₂OH)phenyl, Br, Cl, CN, CH₃, CHF₂, CH₂CH₃, CH₂OCH₃, CH₂OCH₂CH₃,CH(CH₃)₂, CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃, CH₂CH₂OH, CH₂CH(OH)(CH₃), OCH₃,OCH₂CH₃, C(O)NH₂, C(O)CH₃, 2,5-difluorophenyl, 3-pyridinyl, 2-pyridinyl,1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl,1-methyl-1H-pyrazol-5-yl, 1,4-dimethyl-1H-pyrazol-3-yl,1,5-dimethyl-1H-pyrazol-3-yl, 2-methylthiazol-5-yl, cyclohexyl,3-cyanophenyl, 5-methylisoxazol-3-yl, 5-fluoropyridin-3-yl,5-fluoropyridin-2-yl, 3-cyanophenyl, CH₂CN, thiazol-4-yl,6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 6-methylpyridin-2-yl,pyrimidin-2-yl, morpholin-4-yl, cyclopropyl, oxazol-2-yl, CCCH(OH)(CH₃),or C(O)NH(4-fluoro-phenyl).

In some embodiments, each R^(B) is independently unsubstituted phenyl,4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, CH₂(phenyl),CH(CH₂OH)phenyl, Br, CN, CH₃, CH₂CH₃, CH(CH₃)₂, CH(CH₂OH)CH₂CH₃,CH(CH₂OH)CH₃, CH₂CH₂OH, CH₂CH(OH)(CH₃), OCH₃, OCH₂CH₃, C(O)NH₂, C(O)CH₃,2,5-difluorophenyl, 3-pyridinyl, 2-pyridinyl, 1-methyl-1H-pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl,2-methylthiazol-5-yl, cyclohexyl, 3-cyanophenyl, 5-methylisoxazol-3-yl,5-fluoropyridin-3-yl, 3-cyanophenyl, CH₂CN, thiazol-4-yl,6-methylpyridin-3-yl, pyrimidin-2-yl, morpholin-4-yl, cyclopropyl,oxazol-2-yl, CCCH(OH)(CH₃), or C(O)NH(4-fluoro-phenyl).

In some embodiments, each R^(B) is independently unsubstituted phenyl,4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-pyridinyl,CH₂(phenyl), CH(CH₂OH)phenyl, CH₃, CH₂CH₃, CH(CH₃)₂, CH(CH₂OH)CH₂CH₃,CH(CH₂OH)CH₃, CH₂CH₂OH, OCH₃, OCH₂CH₃, or C(O)NH(4-fluoro-phenyl).

In some embodiments, each R^(B) is independently unsubstituted phenyl,4-fluoro-phenyl, CH₂(phenyl), CH(CH₂OH)phenyl, CH₃, CH₂CH₃,CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃, CH₂CH₂OH, OCH₃, OCH₂CH₃, orC(O)NH(4-fluoro-phenyl).

In some embodiments, each R^(B) is independently unsubstituted phenyl,4-fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, CH₂(phenyl),CH(CH₂OH)phenyl, CH₃, CH₂CH₃, CH(CH₃)₂, CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃,CH₂CH₂OH, OCH₃, OCH₂CH₃, or C(O)NH(4-fluoro-phenyl).

In some embodiments, each R^(B) is independently unsubstituted phenyl or4-fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 2-pyridinyl, CH₃,CH₂CH₃ or CH(CH₃)₂. In some embodiments, each R^(B) is independentlyunsubstituted phenyl or 4-fluoro-phenyl, 3-fluoro-phenyl,2-fluoro-phenyl, CH₃, CH₂CH₃ or CH(CH₃)₂. In some embodiments, eachR^(B) is unsubstituted phenyl, CH(CH₃)₂, or 2-pyridinyl. In someembodiments, each R^(B) is independently unsubstituted phenyl or4-fluoro-phenyl. In some embodiments, each R^(B) is unsubstitutedphenyl.

In some embodiments, each R^(B) is 4-fluoro-phenyl. In some embodiments,each R^(B) is pyridinyl (e.g., 2-pyridinyl). In some embodiments, eachR^(B) is independently unsubstituted phenyl or CH(CH₃)₂. In someembodiments, each R^(B) is independently unsubstituted phenyl or CH₂CH₃.In some embodiments, each R^(B) is independently 4-fluoro-phenyl orCH(CH₃)₂. In some embodiments, each R^(B) is independently4-fluoro-phenyl or CH₂CH₃. In some embodiments, each R^(B) isindependently 3-fluoro-phenyl or CH(CH₃)₂. In some embodiments, eachR^(B) is independently 3-fluoro-phenyl or CH₂CH₃. In some embodiments,each R^(B) is independently 2-fluoro-phenyl or CH(CH₃)₂. In someembodiments, each R^(B) is independently 2-fluoro-phenyl or CH₂CH₃.

In some embodiments, Cy^(C) is phenylene optionally substituted by 1, 2,3, or 4 substituents independently selected from R^(C).

In some embodiments, Cy^(C) is

wherein the R^(C) group on the phenylene ring is ortho to thepyrrolo[2,1-f][1,2,4]triazine ring in Formula I.

In some embodiments, each R^(C) is independently selected from OH, halo,C₁₋₄ alkyl, and C₁₋₃ haloalkyl. In some embodiments, each R^(C) isindependently halo or C₁₋₄ alkyl. In some embodiments, each R^(C) isindependently F, Cl, or methyl. In some embodiments, each R^(C) is F.

In some embodiments, Cy^(C) is

wherein R^(C) is F, Cl, or methyl, wherein the phenyl ring is attachedto the pyrrolo[2,1-f][1,2,4]triazine ring at left site of attachment.

In some embodiments, Cy^(C) is

wherein R^(C) is F, wherein the phenyl ring is attached to thepyrrolo[2,1-f][1,2,4]triazine ring at left site of attachment.

In some embodiments, R¹ is

R^(A) is CH₃, CH₂CH₃, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃,C(O)CH(CH₃)₂, C(O)(cyclopropyl), C(O)CH₂CH₃, C(O)CH₂OH, C(O)CH(OH)CH₃,SO₂CH₃, C(O)OCH₃, C(O)N(CH₃)₂, C(O)NHCH₃, C(O)N(CH₂CH₃)₂,C(O)N(CH₃)(CH₂CH₃), or C(O)(morpholin-4-yl);

Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, and Cy^(B)-3 are each optionally substitutedwith 1 or 2 substituents independently selected from R^(B);

each R^(B) is independently unsubstituted phenyl, 4-F-phenyl,3-F-phenyl, 2-F-phenyl, 2-pyridinyl, CH₂(phenyl), CH(phenyl)CH₂OH,methyl, ethyl, isopropyl, CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃, CH₂CH₂OH orOCH₂CH₃;

Cy^(C) is phenylene optionally substituted with 1 R^(C) group; and

R^(C) is F, Cl or Br.

In some embodiments, R¹ is

R^(A) is CH₃, CH₂CH₃, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃, C(O)CH₂OH,C(O)CH(OH)CH₃, SO₂CH₃, C(O)OCH₃, C(O)N(CH₃)₂, C(O)NHCH₃, C(O)N(CH₂CH₃)₂or C(O)N(CH₃)(CH₂CH₃);

Cy^(B) is

wherein Cy^(B)-1 and Cy^(B)-2 are each optionally substituted with 1 or2 substituents independently selected from R^(B);

each R^(B) is independently unsubstituted phenyl, 4-F-phenyl,CH₂(phenyl), CH(phenyl)CH₂OH, methyl, ethyl, CH(CH₂OH)CH₂CH₃,CH(CH₂OH)CH₃, CH₂CH₂OH or OCH₂CH₃;

Cy^(C) is phenylene optionally substituted with 1 R^(C) group; and

R^(C) is F, Cl or Br.

In some embodiments, R¹ is

R^(A) is CH₃, CH₂CH₃, CN, OH, CH₂CH₂OH, CH₂CH₂OCH₃, C(O)CH₃,C(O)CH(CH₃)₂, C(O)CH₂CH₃, C(O)CH₂OH, C(O)CH(OH)CH₃, SO₂CH₃, C(O)OCH₃,C(O)N(CH₃)₂, C(O)NHCH₃, C(O)N(CH₂CH₃)₂, C(O)N(CH₃)(CH₂CH₃), orC(O)(morpholin-4-yl);

Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, and Cy^(B)-3 are each optionally substitutedwith 1 or 2 substituents independently selected from R^(B);

each R^(B) is independently unsubstituted phenyl, 4-F-phenyl,3-F-phenyl, 2-F-phenyl, CH₂(phenyl), CH(phenyl)CH₂OH, methyl, ethyl,isopropyl, CH(CH₂OH)CH₂CH₃, CH(CH₂OH)CH₃, CH₂CH₂OH or OCH₂CH₃;

Cy^(C) is phenylene optionally substituted with 1 R^(C) group; and

R^(C) is F, Cl or Br.

In some embodiments, the heteroaryl group of e.g., Cy^(A), and Cy^(B) isoptionally substituted with an oxo to form a carbonyl. For example, the5-10 membered heteroaryl group of Cy^(B) can be substituted with an oxoto form a carbonyl which includes groups such as 2-pyridone e.g.,

Heteroaryl group can also include substituted pyridone (e.g.,substituted 2-pyridone) such as

In some embodiments: (1) A¹, A², and A³ are each a bond and R^(A) isC₁₋₆ alkyl or (2) A¹ and A² are each a bond, A³ is Cy^(A3), and eachR^(A) is independently selected from C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), and S(O)₂R^(b1); whereinsaid C₁₋₆ alkyl is optionally substituted with a R¹¹ group, providedthat if R^(A) is attached to a nitrogen atom, then R^(A) is not CN orOR^(a1);

each R^(a1), R^(c1), and R^(d1) are independently H or C₁₋₄ alkyl;

each R^(b1) is independently C₁₋₄ alkyl;

each R¹¹ is independently OR^(a3);

R² is H;

R³ is H;

Cy^(B) is a 7,8-dihydroquinoline-2,5(1H,6H)-dione or 2-pyridone ring,which is optionally substituted with 1 or 2 independently selected R^(B)groups;

each R^(B) is independently methyl, ethyl, isopropyl, sec-butyl, orphenyl, each of which is optionally substituted by 1 or 2 independentlyselected R¹² groups;

each R¹² is independently selected from halo, phenyl, and OR^(a4);wherein said phenyl is optionally substituted by 1 or 2 independentlyselected R^(g) group; and

each R^(g) is independently halo;

each R^(a4) is independently H or C₁₋₄ alkyl;

Cy^(C) is phenylene optionally substituted by 1 R^(C) group; and

each R^(C) is independently halo or C₁₋₄ alkyl.

In some embodiments: (1) A¹, A², and A³ are each a bond and R^(A) ismethyl or ethyl; or (2) A¹ and A² are each a bond, A³-R^(A) is selectedfrom

each R^(A) is independently selected from C₁₋₃ alkyl, CN, OH,methylcarbonyl, methoxycarbonyl, N,N-dimethylaminocarbonyl, andmethylsulfonyl, wherein said C₁₋₃ alkyl is optionally substituted with aOH or OCH₃ group, provided that if R^(A) is attached to a nitrogen atom,then R^(A) is not CN or OH;

R² is H;

R³ is H;

Cy^(B) is a 7,8-dihydroquinoline-2,5(1H,6H)-dione or 2-pyridone ring,which is optionally substituted with a R^(B) group;

each R^(B) is independently methyl, ethyl, isopropyl, sec-butyl, orphenyl, each of which is optionally substituted by 1 or 2 independentlyselected R¹² groups;

each R¹² is independently selected from halo, phenyl, and OH; whereinsaid phenyl is optionally substituted by 1 or 2 independently selectedR^(g) group;

each R^(g) is F; and

Cy^(C) is

wherein R^(C) is F, wherein the phenyl ring is attached to thepyrrolo[2,1-f][1,2,4]triazine ring at left site of attachment.

In some embodiments: A¹ and A² are each a bond, A³-R^(A) is,

each R^(A) is independently selected from C₁₋₃ alkyl, methylcarbonyl,ethylcarbonyl, isopropylcarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N,N-(methyl)(ethyl)aminocarbonyl andC(O)[morpholin-4-yl];

R² is H;

R³ is H;

Cy^(B) is a 7,8-dihydroquinoline-2,5(1H,6H)-dione or2,4-dioxo-1,2,3,4-tetrahydropyrimidine ring, which is optionallysubstituted by 1 or 2 independently selected R^(B) groups;

each R^(B) is independently methyl, ethyl, isopropyl, sec-butyl, orphenyl, each of which is optionally substituted by 1 or 2 independentlyselected R¹² groups;

each R¹² is independently selected from halo; and

Cy^(C) is unsubstituted phenylene.

In some embodiments, the present disclosure provides compounds havingFormula (IIa):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIa) are as defined in Formula (I) or any embodiments ofcompounds of Formula (I) as described herein

In some embodiments, the present disclosure provides compounds havingFormula (IIa1) or Formula (IIa2):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIa1) and Formula (IIa2) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein

In some embodiments, the present disclosure provides compounds havingFormula (IIb1) or Formula (IIb2):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIb1) and Formula (IIb2) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein

In some embodiments, the present disclosure provides compounds havingFormula (IIc1) or Formula (IIc2):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIc1) and Formula (IIc2) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein

In some embodiments, the present disclosure provides compounds havingFormula (IId1) or Formula (IId2):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IId1) and Formula (IId2) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IIe1):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIe1) are as defined in Formula (I) or any embodiments ofcompounds of Formula (I) as described herein

In some embodiments, the present disclosure provides compounds havingFormula (IIf1) or Formula (IIf2):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIf1) are as defined in Formula (I) or any embodiments ofcompounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IIg1) or Formula (IIg2):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIg1) and Formula (IIg2) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IIg3), Formula (IIg4), Formula (IIg5):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIg3), Formula (IIg4), and Formula (IIg5) are as defined inFormula (I) or any embodiments of compounds of Formula (I) as describedherein, and t is 0, 1, 2, 3, or 4.

In some embodiments, the present disclosure provides compounds havingFormula (IIh1):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIh1) are as defined in Formula (I) or any embodiments ofcompounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IIi1):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIi1) are as defined in Formula (I) or any embodiments ofcompounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IIIa), Formula (IVa), Formula (Va), Formula (VIa), Formula(VIIa), or Formula (VIIIa):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIIa), Formula (IVa), Formula (Va), Formula (VIa), Formula(VIIa), and Formula (VIIIa) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IIIb), Formula (IVb), Formula (Vb), Formula (VIb), Formula(VIIb), or Formula (VIIIb):

or a pharmaceutically acceptable salt thereof, wherein the variables ofFormula (IIIb), Formula (IVb), Formula (Vb), Formula (VIb), Formula(VIIb), and Formula (VIIIb) are as defined in Formula (I) or anyembodiments of compounds of Formula (I) as described herein.

In some embodiments:

R¹ is A¹-A²-A³-R^(A);

R² is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, cyano-C₁₋₃ alkyl or C₁₋₆ alkoxyalkyl;

R³ is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a), SR^(a),C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)S(O)₂R^(b) orS(O)₂R^(b); wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl are optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, CN, OR^(a), SR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)S(O)₂R^(b), S(O)₂R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)₂NR^(c)R^(d) and Cy^(R3);

A¹ is selected from a bond, Cy^(A1), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

A² is selected from a bond, Cy^(A2), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

A³ is selected from a bond, Cy^(A3), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, —Y—C₁₋₃ alkylene-, and —C₁₋₂ alkylene-Y—C₁₋₂ alkylene-;wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

R^(A) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)OR^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl or C₁₋₆ haloalkyl is optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹¹;

Y is O, S, S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), NR^(f)C(O)NR^(f),NR^(f)S(O)₂NR^(f), S(O)₂NR^(f), NR^(f)S(O)₂, or NR^(f);

each R^(f) is independently selected from H and C₁₋₃ alkyl;

Cy^(A1) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A1);

each R^(A1) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A2) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A2);

each R^(A2) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A3);

each R^(A3) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(R3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(g);

Cy^(C) is phenylene or 5-6 membered heteroarylene; wherein the 5-6membered heteroarylene has at least one ring-forming carbon atom and 1or 2 ring-forming heteroatoms independently selected from N, O, and S;and wherein the phenylene and 5-6 membered heteroarylene are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(C);

each R^(C) is independently selected from OH, CN, halo, C₁₋₄ alkyl, C₁₋₃haloalkyl, C₁₋₄ alkoxy, C₁₋₃ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, carbamyl, C₁₋₄ alkylcarbamyl, di(C₁₋₄alkyl)carbamyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄alkylaminosulfonyl, and di(C₁₋₄ alkyl)aminosulfonyl;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; andwherein the C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B); or

Cy^(B) is 5-10 membered heteroaryl; wherein the 5-10 membered heteroarylhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein: (a) at least one ring-forming carbonatom of the 5-10 membered heteroaryl is substituted by oxo to form acarbonyl group; or (b) the 5-10 membered heteroaryl is substituted byhalo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); and wherein the 5-10 membered heteroaryl isfurther optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(B);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹¹ is independently selected from CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)OR^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)OR^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

R^(a) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R^(b) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(c) and R^(d) are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, phenyl-C₁₋₃alkylene, 5-6 membered heteroaryl-C₁₋₃ alkylene, and 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, phenyl-C₁₋₃ alkylene,5-6 membered heteroaryl-C₁₋₃ alkylene, and 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene are each optionally substituted with 1, 2or 3 substituents independently selected from R^(g);

R^(a1), R^(c1) and R^(d1) are each independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

R^(b1) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R^(e1) is selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²; or

alternatively, any R^(c2) and R^(d2) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,phenyl-C₁₋₄ alkylene, 5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7membered heterocycloalkyl-C₁₋₄ alkylene; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R^(g); or

alternatively, any R^(c3) and R^(d3) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, any R^(c4) and R^(d4) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

provided that:

-   -   1) A³-A²-A³ is not Y—Y when one of A¹, A² or A³ is a bond, or        Y—Y—Y; and    -   2) when A³ is —Y— or —C₁₋₃ alkylene-Y— then R^(A) is H, C₁₋₆        alkyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl or C₁₋₆        haloalkyl is optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹.

In some embodiments:

R¹ is A³-A²-A³-R^(A);

R² is H, halo, CN, C₁₋₄ alkyl, or C₁₋₄ haloalkyl;

R³ is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

A¹ is selected from a bond, Cy^(A1), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, and —Y—C₁₋₃ alkylene-;

A² is selected from a bond, Cy^(A2), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, and —Y—C₁₋₃ alkylene-;

A³ is selected from a bond, Cy^(A3), —Y—, —C₁₋₃ alkylene-, —C₁₋₃alkylene-Y—, and —Y—C₁₋₃ alkylene-;

R^(A) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl or C₁₋₆ haloalkyl isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹;

Y is O, S, S(O), S(O)₂, or C(O);

Cy^(A1) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A1);

each R^(A1) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A2) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A2);

each R^(A2) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkyl sulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(A3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A3);

each R^(A3) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

Cy^(C) is phenylene or 5-6 membered heteroarylene; wherein the 5-6membered heteroarylene has at least one ring-forming carbon atom and 1or 2 ring-forming heteroatoms independently selected from N, O, and S;and wherein the phenylene and 5-6 membered heteroarylene are eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(C);

each R^(C) is independently selected from OH, CN, halo, C₁₋₄ alkyl, C₁₋₃haloalkyl, C₁₋₄ alkoxy, C₁₋₃ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, carbamyl, C₁₋₄ alkylcarbamyl, di(C₁₋₄alkyl)carbamyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄alkylaminosulfonyl, and di(C₁₋₄ alkyl)aminosulfonyl;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; andwherein the C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B); or

Cy^(B) is 6-10 membered aryl or 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein: (a) atleast one ring-forming carbon atom of the 5-10 membered heteroaryl issubstituted by oxo to form a carbonyl group; or (b) the 6-10 memberedaryl or 5-10 membered heteroaryl is substituted by halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)OR^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); andwherein the 6-10 membered aryl or 5-10 membered heteroaryl is furtheroptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)OR^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹¹ is independently selected from CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)OR^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)OR^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

R^(a1), R^(c1) and R^(d1) are each independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

R^(b1) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²; or

alternatively, any R^(c2) and R^(d2) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,phenyl-C₁₋₄ alkylene, 5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7membered heterocycloalkyl-C₁₋₄alkylene; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R^(g); or

alternatively, any R^(c3) and R^(d3) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); or

alternatively, any R^(c4) and R^(d4) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or3 substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

provided that:

-   -   1) A¹-A²-A³ is not Y—Y when one of A¹, A² or A³ is a bond, or        Y—Y—Y; and    -   2) when A³ is —Y— or —C₁₋₃ alkylene-Y— then R^(A) is H, C₁₋₆        alkyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl or C₁₋₆        haloalkyl is optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹.

In some embodiments:

R¹ is A¹-A²-A³-R^(A);

R² is H, halo or C₁₋₄ alkyl;

R³ is H, halo or C₁₋₆ alkyl;

A¹ is selected from a bond, —Y—, and —C₁₋₃ alkylene-;

A² is selected from a bond, —Y—, and —C₁₋₃ alkylene-;

A³ is selected from a bond, Cy^(A3), —Y—, and —C₁₋₃ alkylene-;

R^(A) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl or C₁₋₆ haloalkyl isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹;

Y is O, S, S(O), S(O)₂, or C(O);

Cy^(A3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A3);

each R^(A3) is independently selected from OH, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio,C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, andC₁₋₆ alkoxycarbonyl;

Cy^(C) is phenylene, wherein the phenylene is optionally substituted by1, 2, 3, or 4 substituents independently selected from R^(C);

each R^(C) is independently selected from OH, CN, halo, C₁₋₄ alkyl, C₁₋₃haloalkyl, C₁₋₄ alkoxy, C₁₋₃ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₄ alkylamino, and di(C₁₋₄ alkyl)amino;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; andwherein the C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B); or

Cy^(B) is 6-10 membered aryl or 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein at least onering-forming carbon atom of the 5-10 membered heteroaryl is substitutedby oxo to form a carbonyl group; and wherein the 6-10 membered aryl or5-10 membered heteroaryl is further optionally substituted with 1, 2, 3or 4 substituents independently selected from R^(B);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R¹¹ is independently selected from CN, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

R^(a1), R^(c1) and R^(d1) are each independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R^(b1) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,phenyl-C₁₋₄ alkylene, 5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7membered heterocycloalkyl-C₁₋₄alkylene; wherein said C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, phenyl-C₁₋₄ alkylene,5-6 membered heteroaryl-C₁₋₄ alkylene, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkylene, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

provided that:

-   -   1) A³-A²-A³ is not Y—Y when one of A¹, A² or A³ is a bond, or        Y—Y—Y; and    -   2) when A³ is —Y— or —C₁₋₃ alkylene-Y— then R^(A) is H, C₁₋₆        alkyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl or C₁₋₆        haloalkyl is optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹¹.

In some embodiments:

R¹ is A³-A²-A³-R^(A);

R² is H or C₁₋₄ alkyl;

R³ is H or C₁₋₆ alkyl;

A¹ is selected from a bond and —C₁₋₃ alkylene-;

A² is selected from a bond and —C₁₋₃ alkylene-;

A³ is selected from a bond, Cy^(A3), and —C₁₋₃ alkylene-;

R^(A) is H, C₁₋₆ alkyl, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹¹;

Cy^(A3) is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl; wherein each 5-6 membered heteroaryl and 4-7membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl are each optionally substituted with1, 2, 3 or 4 substituents independently selected from R^(A3);

each R^(A3) is independently selected from OH, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and C₁₋₆ alkoxy;

Cy^(C) is phenylene, wherein the phenylene is optionally substituted by1, 2, 3, or 4 substituents independently selected from R^(C);

each R^(C) is independently selected from OH, CN, halo, C₁₋₄ alkyl, C₁₋₃haloalkyl, C₁₋₄ alkoxy, and C₁₋₃ haloalkoxy;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; andwherein the C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R^(B); or

Cy^(B) is 5-10 membered heteroaryl; wherein the 5-10 membered heteroarylhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein at least one ring-forming carbon atomof the 5-10 membered heteroaryl is substituted by oxo to form a carbonylgroup; and wherein the 5-10 membered heteroaryl is further optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(B);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), andC(O)OR^(a2); wherein said C₁₋₆ alkyl and phenyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R¹¹ is independently selected from CN or OR^(a3);

each R¹² is independently selected from halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), andC(O)OR^(a4); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R^(a1), R^(c1) and R^(d1) are each independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R^(b1) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, each of which isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and phenyl; wherein said C₁₋₆ alkyl and phenylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, and phenyl, each of which is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹²;

each R^(a3) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, phenyl, phenyl-C₁₋₄ alkylene; wherein said C₁₋₆ alkyl,phenyl, and phenyl-C₁₋₄ alkylene are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R^(g);

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, each of which is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments:

R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², and A³ are each a bond,and R^(A) is C₁₋₆ alkyl or C(O)NR^(c1)R^(d1), (2) wherein said A¹ is abond, A² is a bond or —C₁₋₃ alkylene-, A³ is Cy^(A3), and R^(A) is C₁₋₆alkyl, CN, OR^(a1), NR^(c1)R^(d1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), or S(O)₂R^(b1); wherein said C₁₋₆ alkyl of R^(A) isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹, or (3) wherein A¹ is Cy^(A1), A² is a bond or C(O),A³ is Cy^(A3), and R^(A) is H;

R² is H;

R³ is H;

Cy^(A1) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of C₃₋₇ cycloalkyl and 4-7 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup;

Cy^(A3) is C₃₋₇ cycloalkyl, 6 membered heteroaryl, or 4-7 memberedheterocycloalkyl; wherein each 6 membered heteroaryl and 4-7 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of C₃₋₇ cycloalkyl and 4-7 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₃₋₇ cycloalkyl, 6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 C₁₋₆alkyl;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; and wherein the C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R^(B); or

Cy^(B) is 5-10 membered heteroaryl, having one ring-forming carbon atomwhich is substituted with oxo to form a carbonyl group and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-10 memberedheteroaryl is further optionally substituted with 1, 2, 3 or 4substituents independently selected from R^(B);

each R^(B) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkynyl, CN,halo, phenyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkynyl, phenyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently selected from halo and C₁₋₄ alkyl;

each R¹¹ is independently OR^(a3) or C(O)NR^(c3)R^(d3);

each R¹² is independently selected from halo, C₁₋₆ alkyl, CN, phenyl,and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3), R^(d3) and R^(a4) is independently selected from Hand C₁₋₆ alkyl; and

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, and phenyl; wherein said C₁₋₆ alkyl and phenyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹².

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ is abond, A² is a bond or —C₁₋₃ alkylene-, A³ is Cy^(A3), and R^(A) is C₁₋₆alkyl, CN, OR^(a1), NR^(c1)R^(d1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), or S(O)₂R^(b1); wherein said C₁₋₆ alkyl of R^(A) isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl, 6 membered heteroaryl, or 4-7 memberedheterocycloalkyl; wherein each 6 membered heteroaryl and 4-7 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of C₃₋₇ cycloalkyl and 4-7 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group;

Cy^(B) is C₃₋₁₀ cycloalkyl or 4-10 membered heterocycloalkyl; wherein atleast one ring-forming carbon atom of C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; and wherein the C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R^(B); or

Cy^(B) is 5-10 membered heteroaryl, having one ring-forming carbon atomwhich is substituted with oxo to form a carbonyl group and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-10 memberedheteroaryl is further optionally substituted with 1, 2, 3 or 4substituents independently selected from R^(B);

each R^(B) is independently selected from C₁₋₆ alkyl, phenyl, OR^(a2),and C(O)NR^(c2)R^(d2); wherein said C₁₋₆ alkyl and phenyl optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently selected from halo and C₁₋₄ alkyl;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl;

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl;and

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and phenyl; wherein said C₁₋₆ alkyl and phenyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹².

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ andA² are each a bond, A³ is Cy^(A3), and R^(A) is C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of C₃₋₇ cycloalkyl and4-7 membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

Cy^(B) is 5-10 membered heterocycloalkyl; wherein the 5-10 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein at least one ring-forming carbon atom of 5-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; andwherein the 5-10 membered heterocycloalkyl is optionally substitutedwith 1 or 2 substituents independently selected from R^(B); or

Cy^(B) is 5-10 membered heteroaryl, having one ring-forming carbon atomwhich is substituted with oxo to form a carbonyl group and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-10 memberedheteroaryl is further optionally substituted with 1, 2, 3 or 4substituents independently selected from R^(B);

each R^(B) is independently selected from C₁₋₆ alkyl and phenyl; whereinsaid C₁₋₆ alkyl and phenyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ andA² are each a bond, A³ is Cy^(A3), and R^(A) is C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of C₃₋₇ cycloalkyl and4-7 membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

Cy^(B) is 5-6 membered heteroaryl, having one ring-forming carbon atomwhich is substituted with oxo to form a carbonyl group and 1 or 2ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-6 memberedheteroaryl is further optionally substituted with 1 or 2 substituentsindependently selected from R^(B);

each R^(B) is independently selected from C₁₋₆ alkyl and phenyl; whereinsaid C₁₋₆ alkyl and phenyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ andA² are each a bond, A³ is Cy^(A3), and R^(A) is C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of C₃₋₇ cycloalkyl and4-7 membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

Cy^(B) is 5-10 membered heterocycloalkyl; wherein the 5-10 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein at least one ring-forming carbon atom of 5-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; andwherein the 5-10 membered heterocycloalkyl is optionally substitutedwith 1 or 2 substituents independently selected from R^(B); wherein eachR^(B) is independently selected from C₁₋₆ alkyl and phenyl; wherein saidC₁₋₆ alkyl and phenyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ andA² are each a bond, A³ is Cy^(A3), and R^(A) is C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of C₃₋₇ cycloalkyl and4-7 membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

Cy^(B) is 5-10 membered heterocycloalkyl; wherein the 5-10 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein at least one ring-forming carbon atom of 5-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; andwherein the 5-10 membered heterocycloalkyl is optionally substitutedwith 1 or 2 substituents independently selected from R^(B); or

Cy^(B) is 5-10 membered heteroaryl, having one ring-forming carbon atomwhich is substituted with oxo to form a carbonyl group and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-10 memberedheteroaryl is further optionally substituted with 1, 2, 3 or 4substituents independently selected from R^(B);

each R^(B) is independently selected from C₁₋₆ alkyl and phenyl; whereinsaid C₁₋₆ alkyl and phenyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 6-memberedheterocycloalkyl group;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ andA² are each a bond, A³ is Cy^(A3), and R^(A) is C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of C₃₋₇ cycloalkyl and4-7 membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

Cy^(B) is 5-6 membered heteroaryl, having one ring-forming carbon atomwhich is substituted with oxo to form a carbonyl group and 1 or 2ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein the 5-6 memberedheteroaryl is further optionally substituted with 1 or 2 substituentsindependently selected from R^(B);

each R^(B) is independently selected from C₁₋₆ alkyl and phenyl; whereinsaid C₁₋₆ alkyl and phenyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 6-memberedheterocycloalkyl group;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C₁₋₆ alkyl, or (2) wherein said A¹ andA² are each a bond, A³ is Cy^(A3), and R^(A) is C₁₋₆ alkyl, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

R² is H;

R³ is H;

Cy^(A3) is C₃₋₇ cycloalkyl or 4-7 membered heterocycloalkyl; wherein the4-7 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein a ring-forming carbon atom of C₃₋₇ cycloalkyl and4-7 membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

Cy^(B) is 5-10 membered heterocycloalkyl; wherein the 5-10 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein at least one ring-forming carbon atom of 5-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; andwherein the 5-10 membered heterocycloalkyl is optionally substitutedwith 1 or 2 substituents independently selected from R^(B); wherein eachR^(B) is independently selected from C₁₋₆ alkyl and phenyl; wherein saidC₁₋₆ alkyl and phenyl are optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(c);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3);

each R¹² is independently selected from halo, phenyl, and OR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 6-memberedheterocycloalkyl group;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments: R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², andA³ are each a bond, and R^(A) is C(O)NR^(c1)R^(d1) or C₁₋₆ alkyl; or (2)wherein said A¹ is a bond, A² is a bond or —C₁₋₃ alkylene-, A³ isCy^(A3), and R^(A) is H, C₁₋₆ alkyl, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), NR^(c1)R^(d1), C(O)OR^(a1), or S(O)₂R^(b1); whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; (3) wherein A¹ is Cy^(A1),A² is Y, Y is C(O), A³ is Cy^(A3), and R^(A) is H; or (4) wherein A¹ isa bond, A² is Cy^(A2), A³ is Cy^(A3), wherein R^(A) is C₁₋₆ alkyl;

R² is H;

R³ is H;

Cy^(A3) is 5-6 membered heteroaryl, C₃₋₇ cycloalkyl or 4-7 memberedheterocycloalkyl; wherein the 4-7 membered heterocycloalkyl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of C₃₋₇ cycloalkyl and 4-7 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group;

Cy^(B) is 5-10 membered heterocycloalkyl; wherein the 5-10 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein at least one ring-forming carbon atom of 5-10 memberedheterocycloalkyl is substituted by oxo to form a carbonyl group; andwherein the 5-10 membered heterocycloalkyl is optionally substitutedwith 1 or 2 substituents independently selected from R^(B);

each R^(B) is independently selected from halo, CN, C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, and phenyl are optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3) or C(O)NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, C₁₋₆ alkyl, andOR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 6-memberedheterocycloalkyl group;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, Cy^(B) is

wherein Cy^(B)-1, Cy^(B)-2, Cy^(B)-3, Cy^(B)-8, Cy^(B)-9, Cy^(B)-10,Cy^(B)-4, and Cy^(B)-11 are each optionally substituted with 1, 2 or 3independently selected R^(B) groups;

R¹ is A¹-A²-A³-R^(A), (1) wherein said A¹, A², and A³ are each a bond,and R^(A) is C(O)NR^(c1)R^(d1) or C₁₋₆ alkyl; or (2) wherein said A¹ isa bond, A² is a bond or —C₁₋₃ alkylene-, A³ is Cy^(A3), and R^(A) is H,C₁₋₆ alkyl, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)R^(d1),C(O)OR^(a1), or S(O)₂R^(b1); wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹; (3) wherein A¹ is Cy^(A1), A² is Y, Y is C(O), A³ is Cy^(A3), andR^(A) is H; or (4) wherein A¹ is a bond, A² is Cy^(A2), A³ is Cy^(A3),wherein R^(A) is C₁₋₆ alkyl;

R² is H;

R³ is H;

Cy^(A3) is 5-6 membered heteroaryl, C₃₋₇ cycloalkyl or 4-7 memberedheterocycloalkyl; wherein the 4-7 membered heterocycloalkyl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of C₃₋₇ cycloalkyl and 4-7 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group;

each R^(B) is independently selected from halo, CN, C₁₋₆ alkyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, and phenyl are optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

Cy^(C) is phenylene optionally substituted by 1, 2, 3, or 4 substituentsindependently selected from R^(C);

each R^(C) is independently halo;

each R¹¹ is independently OR^(a3) or C(O)NR^(c3)R^(d3);

each R¹² is independently selected from halo, CN, C₁₋₆ alkyl, andOR^(a4);

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl;

alternatively, R^(c1) and R^(d1) attached to the same N atom, togetherwith the N atom to which they are attached, form a 6-memberedheterocycloalkyl group;

each R^(b1) is independently selected from C₁₋₆ alkyl; and

each R^(a3) and R^(a4) is independently selected from H and C₁₋₆ alkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub combination.

At various places in the present specification, substituents ofcompounds provided herein are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached any ring member provided that thevalency of the atom is not exceeded. For example, an azetidine ring maybe attached at any position of the ring, whereas an azetidin-3-yl ringis attached at the 3-position.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds provided herein in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R. In another example,when an optionally multiple substituent is designated in the form:

then it is to be understood that substituent R can occur p number oftimes on the ring, and R can be a different moiety at each occurrence.It is to be understood that each R group may replace any hydrogen atomattached to a ring atom, including one or both of the (CH₂)_(n) hydrogenatoms. Further, in the above example, should the variable Q be definedto include hydrogens, such as when Q is said to be CH₂, NH, etc., anyfloating substituent such as R in the above example, can replace ahydrogen of the Q variable as well as a hydrogen in any othernon-variable component of the ring.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylene”, employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1,-diyl,propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl,butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In someembodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Examples of alkylamino groups include, but are not limited to,N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino andN-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino andN-(tert-butyl)amino), and the like.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms. Examples of alkoxycarbonyl groups include, but are notlimited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g.,n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g.,n-butoxycarbonyl and tert-butoxycarbonyl), and the like.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Examples of alkylcarbonyl groups include, but are not limited to,methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyland isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl andtert-butyl carbonyl), and the like.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms.

In some embodiments, each alkyl group has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(═O)— group, which may also be writtenas C(O).

As used herein, the term “carboxy” refers to a —C(O)OH group.

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “HO—C1-3 alkyl” refers to a group of formula—(C1-3 alkylene)-OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,halo is F, Cl, or Br. In some embodiments, halo is F or Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Ring-forming carbon atoms of a cycloalkyl group can beoptionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Alsoincluded in the definition of cycloalkyl are moieties that have one ormore aromatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo or thienyl derivatives ofcyclopentane, cyclohexane, and the like. A cycloalkyl group containing afused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Cycloalkylgroups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C₃₋₁₀).In some embodiments, the cycloalkyl is a C₃₋₁₀ monocyclic or bicycliccycloalkyl. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₃₋₁₀ monocyclic orbicyclic non-aromatic carbocycle, which optionally has ring memberswhich have oxo (═O) or sulfido (═S) substitution and which optionallyhas a phenyl or 5-6 membered aromatic heterocycle fused to thenon-aromatic portion of the ring structure, wherein the heterocycle has1-3 ring members independently selected from N, S, or O. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic non-aromaticcarbocycle, which optionally has ring members which have oxo (═O) orsulfido (═S) substitution and which optionally has a phenyl or 5-6membered aromatic heterocycle fused to the non-aromatic portion of thering structure, wherein the heterocycle has 1-3 ring membersindependently selected from N, S, or O. In some embodiments, thecycloalkyl is a C₃₋₇ monocyclic cycloalkyl. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcaranyl, and the like. In some embodiments,cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). Examplesof aryl rings include, but are not limited to, phenyl, 1-naphthyl,2-naphthyl, and the like. In some embodiments, aryl groups have from 6to 10 carbon atoms or 6 carbon atoms. In some embodiments, the arylgroup is a monocyclic or bicyclic group. In some embodiments, the arylgroup is phenyl or naphthyl. In some embodiments, the aryl group isphenyl.

As used herein, the term “phenylene”, refers to a divalent phenyllinking group. In some embodiments, the phenylene is optionallysubstituted as described herein.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In one embodiment theheteroaryl group is a 5 to 10 membered heteroaryl group. In anotherembodiment the heteroaryl group is a 5 to 6 membered heteroaryl group.In certain embodiments, the heteroaryl group is a monocyclic or bicyclicaromatic ring system having 5 to 10 ring-forming atoms, wherein 1 to 4ring-forming atoms are heteroatoms independently selected from N, O, andS, wherein the N and S as ring members are each optionally oxidized, thecarbon ring members may be optionally replaced by carbonyl. In anotherpreferred embodiment, the heteroaryl group is a monocyclic aromatic ringsystem having 5 to 6 ring-forming atoms, wherein 1 to 4 ring-formingatoms are heteroatoms independently selected from N, O, and S, whereinthe N and S as ring members are each optionally oxidized, the carbonring members may be optionally replaced by carbonyl.

In some embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl, pyridone, uracil and pyridazinyl. In someembodiments, pyridone is substituted e.g., 1-methylpyridin-2(1H)-one and1-phenylpyridin-2(1H)-one. In some embodiments, uracil is substitutedwith, e.g., phenyl, isopropyl, and pyridinyl. In some embodiments,uracil is substituted with phenyl and isopropyl, e.g.,1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine. In someembodiments, uracil is substituted with pyridinyl and isopropyl, e.g.,1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine.

As used herein, the term “heteroarylene”, refers to a divalentheteroaryl linking group. In some embodiments, the heteroarylene isoptionally substituted as described herein.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups.Heterocycloalkyl groups can also include spirocycles. Exampleheterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbonatoms and heteroatoms of a heterocycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.).The heterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the cycloalkyl ring, for example, benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl group is a morpholinering, pyrrolidine ring, piperazine ring, piperidine ring, dihydropyranring, tetrahydropyran ring, tetrahydropyridine, azetidine ring, ortetrahydrofuran ring. In certain embodiments, the heterocycloalkyl groupis a monocyclic or bicyclic non-aromatic ring or ring system having 4 to10 ring-forming atoms, wherein 1 to 4 ring-forming atoms are heteroatomsindependently selected from N, O, and S, wherein the N and S as ringmembers are each optionally oxidized, the carbon ring members may beoptionally replaced by carbonyl, and the heterocycloalkyl group can beoptionally fused to a 5-6 membered heteroaryl or phenyl ring, whereinthe 5-6 membered heteroaryl ring may have 1-3 heteroatom ring membersindependently selected from N, S, and O. In another embodiment, theheterocycloalkyl group is a monocyclic non-aromatic ring or ring systemhaving 4 to 6 ring-forming atoms, wherein 1 to 2 ring-forming atoms areheteroatoms independently selected from N, O, and S, wherein the N and Sas ring members are each optionally oxidized, the carbon ring membersmay be optionally replaced by carbonyl, and the heterocycloalkyl groupcan be optionally fused to a 5-6 membered heteroaryl or phenyl ring,wherein the 5-6 membered heteroaryl ring may have 1-3 heteroatom ringmembers independently selected from N, S, and O. In some embodiments, a10-membered heterocycloalkyl group is7,8-dihydroquinoline-2,5(1H,6H)-dione. In some embodiments, a 6-memberedheterocycloalkyl group is piperidinyl, piperazinyl, ortetrahydropyranyl.

In some embodiments, the aryl group (e.g., phenyl), heteroaryl group,heterocycloalkyl group, or cycloalkyl group as used herein (e.g., invariables Cy^(A1), Cy^(A2), Cy^(A3), Cy^(C) etc.) can be a terminalgroup or an internal group (e.g., a divalent linker). In someembodiments, the terms aryl, heteroaryl, heterocycloalkyl, andcycloalkyl and their corresponding arylene, heteroarylene,heterocycloalkylene and cycloalkylene terms are used interchangeably. Askilled artisan would readily recognize whether such a group is aterminal substituent or a linker based on the structure, thesubstituents described herein, and the context in which such a termappears. For example, even though the disclosure may list phenyl in thedefinition of variables such as Cy^(A2), depending on the substitutionpattern, the disclosure also covers phenylene groups.

As used herein, “C_(n-m) cycloalkyl-C_(o-p) alkylene” refers to a groupof formula -alkylene-cycloalkyl, wherein the cycloalkyl group has n to mring members and the alkylene group has o to p carbon atoms.

As used herein, “C_(n-m) heterocycloalkyl-C_(o-p) alkylene” refers to agroup of formula -alkylene-heterocycloalkyl, wherein theheterocycloalkyl group has n to m ring members and the alkylene grouphas o to p carbon atoms.

As used herein, “phenyl-C_(o-p) alkylene” refers to a group of formula-alkylene-phenyl, wherein the alkylene group has o to p carbon atoms.

As used herein, “C_(n-m) aryl-C_(o-p) alkylene” refers to a group offormula -alkylene-aryl, wherein the aryl group has n to m ring membersand the alkylene group has o to p carbon atoms.

As used herein, “C_(n-m) heteroaryl-C_(o-p) alkylene” refers to a groupof formula -alkylene-heteroaryl, wherein the heteroaryl group has n to mring members and the alkylene group has o to p carbon atoms.

As used herein, the term “oxo” refers to an oxygen atom as a divalentsubstituent, forming a carbonyl group when attached to a carbon (e.g.,C═O), or attached to a heteroatom forming a sulfoxide or sulfone group.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present disclosure. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as□-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids and include, but are notlimited to, strong and weak acids. Some example acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid,benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weakacids include, but are not limited to acetic acid, propionic acid,butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoicacid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, potassium carbonate, andsodium bicarbonate. Some example strong bases include, but are notlimited to, hydroxide, alkoxides, metal amides, metal hydrides, metaldialkylamides and arylamines, wherein; alkoxides include lithium, sodiumand potassium salts of methyl, ethyl and t-butyl oxides; metal amidesinclude sodium amide, potassium amide and lithium amide; metal hydridesinclude sodium hydride, potassium hydride and lithium hydride; and metaldialkylamides include lithium, sodium, and potassium salts of methyl,ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, trimethylsilyl andcyclohexyl substituted amides.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J. MedChem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd Radiopharm. 2015,58, 308-312).

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present disclosure also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present disclosureinclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(7-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc, (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethyl amine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph(phenyl); pM (picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphorylchloride); RP-HPLC (reverse phase high performance liquidchromatography); s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg(microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weightpercent).

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the TAM kinases with a compound of the disclosureincludes the administration of a compound of the present disclosure toan individual or patient, such as a human, having TAM, as well as, forexample, introducing a compound of the disclosure into a samplecontaining a cellular or purified preparation containing the TAMkinases.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)inhibiting the disease; for example, inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),or 2) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology).

As used herein the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Synthesis

Compounds provided herein, including salts thereof, can be preparedusing known organic synthesis techniques and according to variouspossible synthetic routes.

The reactions for preparing compounds provided herein can be carried outin suitable solvents which can be readily selected by one of skill inthe art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds provided herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature”, “room temperature”, and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds as disclosed herein can be prepared by one skilled in the artaccording to preparatory routes known in the literature and according tovarious possible synthetic routes. Example synthetic methods forpreparing compounds of the present application are provided in Scheme 1below.

The reactions for preparing compounds provided herein can be carried outin suitable solvents which can be readily selected by one of skill inthe art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds provided herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature”, “room temperature”, and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds as disclosed herein can be prepared by one skilled in the artaccording to preparatory routes known in the literature. A compound ofFormula I can be prepared according to Scheme 1. Compounds (i) can beprepared by standard Suzuki coupling of bromides (i-a) with boronicesters or acids (i-b), wherein R¹ contains the alkenylene functionality.Catalytic hydrogenation of the R¹ functional group using Pd on carbon oranother suitable catalyst can then provide compounds (ii) wherein R¹contains the alkylene functionality. Selective bromination of compound(ii) using, e.g., NBS, yields bromides (iii) which are then directlytreated with boronic esters or acids (iv) under, e.g., standard Suzukicoupling conditions, to afford compounds of Formula I. Alternatively,compounds of Formula I can be prepared through Suzuki coupling ofbromides (iii) with boronic esters or acids (v) followed by reaction ofthe resultant amines (vi) with carboxylic acids (vii), and a suitablecoupling reagent such as HATU or BOP.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof TAM kinases as described below.

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

TAM Kinases

Receptor tyrosine kinases (RTKs) are cell surface proteins that transmitsignals from the extracellular environment to the cell cytoplasm andnucleus to regulate cellular events such as survival, growth,proliferation, differentiation, adhesion and migration. All RTKs containan extracellular ligand binding domain and a cytoplasmic proteintyrosine kinase domain. Ligand binding leads to the dimerization ofRTKs, which triggers the activation of the cytoplasmic kinase andinitiates downstream signal transduction pathways. RTKs can beclassified into distinct subfamilies based on their sequence similarity.The TAM subfamily consists of three RTKs including TYRO3, AXL and MER(Graham et al., 2014, Nature reviews Cancer 14, 769-785; and Linger etal., 2008, Oncogene 32, 3420-3431). TAM kinases are characterized by anextracellular ligand binding domain consisting of twoimmunoglobulin-like domains and two fibronectin type III domains. Twoligands, growth arrest specific 6 (GAS6) and protein S (ProS), have beenidentified for TAM kinases. GAS6 can bind to and activate all three TAMkinases, while ProS is a ligand for MER and TYRO3 (Graham et al., 2014,Nature reviews Cancer 14, 769-785).

TAM kinases are over-expressed in many cancers and play important rolesin tumor initiation and maintenance; therefore, TAM inhibitionrepresents an attractive approach for targeting another class ofoncogenic RTKs (Graham et al., 2014, Nature reviews Cancer 14, 769-785;and Linger et al., 2008, Oncogene 32, 3420-3431).

Axl was originally identified as a transforming gene from DNA ofpatients with chronic myelogenous leukemia (O'Bryan et al., 1991,Molecular and cellular biology 11, 5016-5031). GAS6 binds to Axl andinduces subsequent auto-phosphorylation and activation of Axl tyrosinekinase. Axl activates several downstream signaling pathways includingPI3K-Akt, Raf-MAPK, PLC-PKC (Feneyrolles et al., 2014, Molecular cancertherapeutics 13, 2141-2148; Linger et al., 2008, Oncogene 32,3420-3431). AXL is over-expressed or amplified in a variety ofmalignancies including lung cancer, prostate cancer, colon cancer,breast cancer, melanoma, and renal cell carcinoma (Linger et al., 2008,Oncogene 32, 3420-3431). Over-expression of AXL is correlated with poorprognosis (Linger et al., 2008, Oncogene 32, 3420-3431). As a result,AXL activation promotes cancer cell survival, proliferation,angiogenesis, metastasis, and resistance to chemotherapy and targetedtherapies. AXL knockdown or AXL antibody can inhibit the migration ofbreast cancer and NSCLC cancer in vitro, and blocked tumor growth inxenograft tumor models (Li et al., 2009, Oncogene 28, 3442-3455). Inpancreatic cancer cells, inhibition of AXL decreased cell proliferationand survival (Koorstra et al., 2009, Cancer biology & therapy 8,618-626). In prostate cancer, AXL inhibition decreased cell migration,invasion, and proliferation (Tai et al., 2008, Oncogene 27, 4044-4055).In addition, AXL over-expression or amplification is a major mechanismfor resistance to EGFR inhibitors by lung cancer cells, and AXLinhibition can reverse the resistance (Zhang et al., 2012, Naturegenetics 44, 852-860).

Mer was originally identified as a phospho-protein from a lymphoblastoidexpression library (Graham et al., 1995, Oncogene 10, 2349-2359). BothGAS6 and ProS can bind to Mer and induce the phosphorylation andactivation of Mer kinase (Lew et al., 2014. eLife, 3:e03385). Like Axl,Mer activation also conveys downstream signaling pathways includingPI3K-Akt and Raf-MAPK (Linger et al., 2008, Oncogene 32, 3420-3431). MERis over-expressed in many cancers including multiple myeloma, gastric,prostate, breast, melanoma and rhabdomyosarcoma (Linger et al., 2008,Oncogene 32, 3420-3431). MER knockdown inhibits multiple myeloma cellgrowth in vitro and in xenograft models (Waizenegger et al., 2014,Leukemia, 1-9). In acute myeloid leukemia, MER knockdown inducedapoptosis, decreased colony formation, and increased survival in a mousemodel (Lee-Sherick et al., 2013, Oncogene 32, 5359-5368). MER inhibitionincreased apoptosis, decreased colony formation, increasedchemo-sensitivity, and decreased tumor growth in NSCLC (Linger et al.,2013, Oncogene 32, 3420-3431). Similar effects are observed for MERknockdown in melanoma (Schlegel et al., 2013) and glioblastoma (Wang etal., 2013, Oncogene 32, 872-882).

Tyro3 was originally identified through a PCR-based cloning study (Laiand Lemke, 1991, Neuron 6, 691-704). Both ligands, GAS6 and ProS, canbind to and activate Tyro3. TYRO3 also plays a role in cancer growth andproliferation. TYRO3 is over-expressed in melanoma cells, and knockdownof TYRO3 induces apoptosis in these cells (Demarest et al., 2013,Biochemistry 52, 3102-3118).

In addition to their role as transforming oncogenes, TAM kinases haveemerged as potential immune-oncology targets. The durable clinicalresponses to immune checkpoint blockade observed in cancer patientsclearly indicate that the immune system plays a critical role in tumorinitiation and maintenance. Genetic mutations from cancer cells canprovide a diverse set of antigens that the immune cells can use todistinguish tumor cells from their normal counterpart. However, cancercells have evolved multiple mechanisms to evade host immunesurveillance. In fact, one hallmark of human cancer is its ability toavoid immune destruction. Cancer cells can induce an immune-suppressivemicroenvironment by promoting the formation of M2 tumor associatedmacrophages, myeloid derived suppressor cells (MDSC), and regulatory Tcells. Cancer cells can also produce high levels of immune checkpointproteins such as PD-L1 to induce T cell anergy or exhaustion. It is nowclear that tumors co-opt certain immune-checkpoint pathways as a majormechanism of immune resistance (Pardoll, 2012, Cancer 72, 252-264).Antagonizing these negative regulators of T-cell function withantibodies has shown striking efficacy in clinical trials of a number ofmalignancies including advanced melanoma, non-small cell lung andbladder cancer. While these therapies have shown encouraging results,not all patients mount an anti-tumor response suggesting that otherimmune-suppressive pathways may also be important.

TAM kinases have been shown to function as checkpoints for immuneactivation in the tumor milieu. All TAM kinases are expressed in NKcells, and TAM kinases inhibit the anti-tumor activity of NK cells.LDC1267, a small molecule TAM inhibitor, activates NK cells, and blocksmetastasis in tumor models with different histologies (Paolino et al.,2014, Nature 507, 508-512). In addition, MER kinase promotes theactivity of tumor associated macrophages through the increased secretionof immune suppressive cytokines such as IL10 and IL4, and decreasedproduction of immune activating cytokines such as IL12 (Cook et al.,2013, The Journal of clinical investigation 123, 3231-3242). MERinhibition has been shown to reverse this effect. As a result, MERknockout mice are resistant to PyVmT tumor formation (Cook et al., 2013,The Journal of clinical investigation 723, 3231-3242). The role of TAMkinases in the immune response is also supported by knockout mousestudies. TAM triple knockout mice (TKO) are viable. However, these micedisplayed signs of autoimmune disease including enlarged spleen andlymph nodes, autoantibody production, swollen footpad and joints, skinlesions, and systemic lupus erythematosus (Lu and Lemke, 2001, Science293, 306-311). This is consistent with the knockout phenotype forapproved immune-oncology targets such as CTLA4 and PD-1. Both CTLA-4 andPD-1 knockout mice showed signs of autoimmune disease, and these micedie within a few weeks after birth (Chambers et al., 1997, Immunity 7,885-895; and Nishimura et al., 2001, Science 297, 319-322).

TAM inhibition will have not only direct activity against neoplasticcells, but also activate the anti-cancer immune response. Thus TAMinhibitors represent an attractive approach for the treatment of canceras single agents. In addition, TAM inhibitors may be combined with othertargeted therapies, chemotherapies, radiation, or immunotherapeuticagents to achieve maximal efficacy in the clinic.

Methods of Use

Compounds of the present disclosure can modulate or inhibit the activityof TAM kinases. For example, the compounds of the disclosure can be usedto inhibit activity of a TAM kinase in a cell or in an individual orpatient in need of inhibition of the kinases by administering aninhibiting amount of a compound of the disclosure to the cell,individual, or patient.

In some embodiments, the compounds of the disclosure are selective forthe TAM kinases over one or more of other kinases. In some embodiments,the compounds of the disclosure are selective for the TAM kinases overother kinases. In some embodiments, the selectivity is 2-fold or more,3-fold or more, 5-fold or more, 10-fold or more, 25-fold or more,50-fold or more, or 100-fold or more.

The compounds of the invention can inhibit one or more of AXL, MER andTYRO3. In some embodiments the compounds are selective for one TAMkinase over another. “Selective” means that the compound binds to orinhibits a TAM kinase with greater affinity or potency, respectively,compared to a reference enzyme, such as another TAM kinase. For example,the compounds can be selective for AXL over MER and TYRO3, selective forMER over AXL and TYRO3, or selective for AXL and MER over TYRO3. In someembodiments, the compounds inhibit all of the TAM family members (e.g.,AXL, MER and TYRO3). In some embodiments, the compounds can be selectivefor AXL and MER over TYRO3 and other kinases. In some embodiments,provided herein is a method for inhibiting AXL and MER kinase, whichcomprises contacting the AXL and MER kinase with a compound providedherein, or a pharmaceutically acceptable salt thereof.

As TAM kinases inhibitors, the compounds of the disclosure are useful inthe treatment of various diseases associated with abnormal expression oractivity of the TAM kinases. Compounds which inhibit TAM kinases will beuseful in providing a means of preventing the growth or inducingapoptosis in tumors, particularly by inhibiting angiogenesis. It istherefore anticipated that the compounds will prove useful in treatingor preventing proliferative disorders such as cancers. In particular,tumours with activating mutants of receptor tyrosine kinases orupregulation of receptor tyrosine kinases may be particularly sensitiveto the inhibitors.

In certain embodiments, the disclosure provides a method for treating adisease or disorder mediated by TAM kinases in a patient in needthereof, comprising the step of administering to said patient a compoundprovided herein, or a pharmaceutically acceptable composition thereof.

For example, the compounds of the disclosure are useful in the treatmentof cancer. Example cancers include bladder cancer, breast cancer,cervical cancer, colorectal cancer, cancer of the small intestine, coloncancer, rectal cancer, cancer of the anus, endometrial cancer, gastriccancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx,nasopharynx, oropharynx, lips, and mouth), kidney cancer, liver cancer(e.g., hepatocellular carcinoma, cholangiocellular carcinoma), lungcancer (e.g., adenocarcinoma, small cell lung cancer and non-small celllung carcinomas, parvicellular and non-parvicellular carcinoma,bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma),ovarian cancer, prostate cancer, testicular cancer, uterine cancer,esophageal cancer, gall bladder cancer, pancreatic cancer (e.g. exocrinepancreatic carcinoma), stomach cancer, thyroid cancer, parathyroidcancer, skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma,Merkel cell skin cancer), and brain cancer (e.g., astrocytoma,medulloblastoma, ependymoma, neuro-ectodermal tumors, pineal tumors).

Other cancers treatable with the compounds of the disclosure includebone cancer, intraocular cancers, gynecological cancers, cancer of theendocrine system, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, pituitary cancer,triple-negative breast cancer (TNBC) and environmentally induced cancersincluding those induced by asbestos.

Further example cancers include hematopoietic malignancies such asleukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma,adult T cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acutemyelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma,myeloproliferative neoplasms (e.g., polycythemia vera, essentialthrombocythemia, and primary myelofibrosis), Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma,acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt'slymphoma.

Other cancers treatable with the compounds of the disclosure includetumors of the eye, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma,and osteosarcoma.

Compounds of the disclosure can also be useful in the inhibition oftumor metastasis.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML),diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL),marginal zone lymphoma (MZL), Non-Hodgkin lymphoma (including relapsedor refractory NHL), follicular lymphoma (FL), Hodgkin lymphoma,lymphoblastic lymphoma, myeloproliferative diseases (e.g., primarymyelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis(ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblasticlymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma,peripheral T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), colorectal cancer and bile duct cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma, urothelial carcinoma), prostate(adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma, Lhermitte-Duclos disease, neoplasmof the central nervous system (CNS), primary CNS lymphoma and spinalaxis tumor.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, the present disclosure provides a method fortreating hepatocellular carcinoma in a patient in need thereof,comprising the step of administering to said patient a compound ofFormula (I) or a compound as disclosed herein, or a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound ofFormula (I) or a compound as disclosed herein.

In some embodiments, the present disclosure provides a method fortreating Rhabdomyosarcoma, esophageal cancer, breast cancer, or cancerof a head or neck, in a patient in need thereof, comprising the step ofadministering to said patient a compound Formula (I) or a compound asdisclosed herein, or a pharmaceutically acceptable salt thereof, or acomposition comprising a compound of Formula (I) or a compound asdisclosed herein.

In some embodiments, the present disclosure provides a method oftreating cancer, wherein the cancer is selected from hepatocellularcancer, breast cancer, bladder cancer, colorectal cancer, melanoma,mesothelioma, lung cancer, prostate cancer, pancreatic cancer,testicular cancer, thyroid cancer, squamous cell carcinoma,glioblastoma, neuroblastoma, uterine cancer, and rhabdosarcoma.

Targeting TAM receptor tyrosine kinases can provide a therapeuticapproach to treat viral diseases (T Shibata, et. al. The Journal ofImmunology, 2014, 192, 3569-3581). The present disclosure provides amethod for treating infections such as viral infections. The methodincludes administering to a patient in need thereof, a therapeuticallyeffective amount of a compound of Formula (I) or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, a salt thereof. Examples of viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, human immunodeficiency virus, human papillomavirus, influenza,hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplexviruses, human cytomegalovirus, severe acute respiratory syndrome virus,ebola virus, Marburg virus and measles virus. In some embodiments,viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to, hepatitis (A, B, or C), herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Ban-virus),adenovirus, influenza virus, flaviviruses (for example: West Nile,dengue, tick-borne encephalitis, yellow fever, Zika), echovirus,rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus,mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus,vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscumvirus, poliovirus, rabies virus, JC virus and arboviral encephalitisvirus.

In some embodiments, the present disclosure provides a method fortreating thrombus formation (J. M. E. M. Cosemans et. al. J. ofThrombosis and Haemostasis 2010, 8, 1797-1808 and A. Angelillo-Scherreret. al. J. Clin. Invest. 2008, 118, 583-596).

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc), and/or tyrosine kinase inhibitors can be used in combination withthe compounds of Formula (I) or a compound as described herein fortreatment of TAM-associated diseases, disorders or conditions. Theagents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with the compounds of the presentapplication for the treatment of cancer include chemotherapeutic agents,targeted cancer therapies, immunotherapies or radiation therapy.Compounds of this application may be effective in combination withanti-hormonal agents for treatment of breast cancer and other tumors.Suitable examples are anti-estrogen agents including but not limited totamoxifen and toremifene, aromatase inhibitors including but not limitedto letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds of the present disclosure. These include anti-androgensincluding but not limited to flutamide, bicalutamide, and nilutamide,luteinizing hormone-releasing hormone (LHRH) analogs includingleuprolide, oserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

Compounds of the present disclosure may be combined with or in sequencewith other agents against membrane receptor kinases especially forpatients who have developed primary or acquired resistance to thetargeted therapy. These therapeutic agents include inhibitors orantibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, PDGFR, FGFR1,FGFR2, FGFR3, FGFR4, TrkA, TrkB, TrkC, ROS, c-Kit, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with TAM inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against FGFRs include butnot limited to AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, and Debio1347. Agentsagainst Trks include but not limited to LOXO-101 and RXDX-101. Agentsagainst Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, andponatinib and those against Alk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith TAM inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compounds ofthe present disclosure include inhibitors of the PBK-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway,inhibitors of Pim kinases, and inhibitors of protein chaperones and cellcycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib, idelalisib, buparlisib, and IPI-549. In some embodiments,the PI3K inhibitor is selective for PI3K alpha, PI3K beta, PI3K gamma orPI3K delta. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with TAM kinasesinhibitors. Other suitable examples include but are not limited tovemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetiniband GDC-0973 (MEK inhibitors). Inhibitors of one or more JAKs (e.g.,ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin),cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), andproteasomes (e.g., bortezomib, carfilzomib) can also be combined withcompounds of the present disclosure. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3. Agents against Pimkinases include but not limited to LGH447, INCB053914, and SGI-1776.

Other suitable agents for use in combination with the compounds of thepresent disclosure include chemotherapy combinations such asplatinum-based doublets used in lung cancer and other solid tumors(cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatinplus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin orcarboplatin plus pemetrexed) or gemcitabine plus paclitaxel boundparticles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with the compounds of thepresent disclosure include: dacarbazine (DTIC), optionally, along withother chemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds provided herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) inhibitors.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents include CSF1R inhibitors (PLX3397, LY3022855,etc.) and CSF1R antibodies (IMC-CS4, RG7155, etc.).

Other anti-cancer agents include BET inhibitors (INCB054329, OTX015,CPI-0610, etc.), LSD1 inhibitors (GSK2979552, INCB059872, etc), HDACinhibitors (panobinostat, vorinostat, etc), DNA methyl transferaseinhibitors (azacitidine and decitabine), and other epigeneticmodulators.

Other anti-cancer agents include Bcl2 inhibitor ABT-199, and other Bcl-2family protein inhibitors.

Other anti-cancer agents include TGF beta receptor kinase inhibitor suchas LY2157299.

Other anti-cancer agents include BTK inhibitor such as ibrutinib.

Other anti-cancer agents include beta catenin pathway inhibitors, notchpathway inhibitors and hedgehog pathway inhibitors.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

One or more additional immune checkpoint inhibitors can be used incombination with a compound as described herein for treatment ofTAM-associated diseases, disorders or conditions. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96,TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpointmolecule is a stimulatory checkpoint molecule selected from CD27, CD28,CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, CD96,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab, pembrolizumab, or PDR001. In some embodiments, the anti-PD1antibody is pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) orMEDI4736 (durvalumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN01876 or MK-1248.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.In some embodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

The compounds of the present disclosure can be combined with anotherimmunogenic agent, such as cancerous cells, purified tumor antigens(including recombinant proteins, peptides, and carbohydrate molecules),cells, and cells transfected with genes encoding immune stimulatingcytokines. Non-limiting examples of tumor vaccines that can be usedinclude peptides of melanoma antigens, such as peptides of gp100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination witha vaccination protocol for the treatment of cancer. In some embodiments,the tumor cells are transduced to express GM-CSF. In some embodiments,tumor vaccines include the proteins from viruses implicated in humancancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBVand HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments,the compounds of the present disclosure can be used in combination withtumor specific antigen such as heat shock proteins isolated from tumortissue itself. In some embodiments, the compounds of the presentdisclosure can be combined with dendritic cells immunization to activatepotent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fc alpha or Fc gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination witharginase inhibitors, for example CB-1158.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of the present disclosure can be used as anticoagulant assingle agent or in combination with other anticoagulants including butnot limited to apixaban, dabigatran, edoxaban, fondaparinex, heparin,rivaroxaban, and warfarin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds provided herein can beadministered in the form of pharmaceutical compositions which refers toa combination of a compound provided herein, or its pharmaceuticallyacceptable salt, and at least one pharmaceutically acceptable carrier.These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This application also includes pharmaceutical compositions whichcontain, as the active ingredient, one or more of the compounds providedherein in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the present disclosure, theactive ingredient is typically mixed with an excipient, diluted by anexcipient or enclosed within such a carrier in the form of, for example,a capsule, sachet, paper, or other container. When the excipient servesas a diluent, it can be a solid, semi-solid, or liquid material, whichacts as a vehicle, carrier or medium for the active ingredient. Thus,the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, suppositories, sterile injectablesolutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the present disclosure can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

The compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present disclosure canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound provided hereinin a pharmaceutical composition can vary depending upon a number offactors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds provided herein can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds provided herein can also be formulated in combination withone or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to fluorescent dye,spin label, heavy metal or radio-labeled compounds provided herein thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the TAM kinases in tissuesamples, including human, and for identifying TAM kinases ligands byinhibition binding of a labeled compound. Accordingly, the presentdisclosure includes TAM kinases assays that contain such labeledcompounds.

The present disclosure further includes isotopically-labeled compoundsof the invention. An “isotopically” or “radio-labeled” compound is acompound provided herein where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro TAM kinases labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds provided herein and are well knownin the art.

A radio-labeled compound provided herein can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the application to the TAM kinases. Accordingly, the abilityof a test compound to compete with the radio-labeled compound forbinding to the TAM kinases directly correlates to its binding affinity.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7 or 8deuterium atoms. Synthetic methods for including isotopes into organiccompounds are known in the art.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of TAM-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound providedherein. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof TAM kinases as described below.

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

EXAMPLES Example 1.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Step 1: N-[(2,6-Dioxocyclohexylidene)methyl]urea

To a mixture of 1,3-cyclohexanedione (from Aldrich, 500 mg, 4.46 mmol)and urea (268 mg, 4.46 mmol) dissolved in N,N-dimethylformamide (1.73 mLat 50° C.), was added ethyl orthoformate (1.11 mL, 6.69 mmol) and aceticacid (8.9 mL). The reaction mixture was heated in a sealed tube at 90°C. for 3 h. The reaction mixture was cooled, concentrated under vacuum,and left at rt for crystallization. The resulting precipitate wasfiltered by vacuum and the cake was washed with cold sec-BuOH to givethe desired product as off-white powders (536 mg, 66%). LCMS calcd forC₈H₁₁N₂O₃ (M+H)⁺: m/z=183.1. Found: 183.1.

Step 2: Methyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate

N-[(2,6-Dioxocyclohexylidene)methyl]urea (50 mg, 0.27 mmol) wasdissolved in dry N,N-dimethylformamide (0.54 mL), followed by theaddition of acetic acid, cyanomethyl ester (35.4 mg, 0.36 mmol) andpotassium tert-butoxide (61.6 mg, 0.55 mmol) with stirring. The reactionmixture was heated at 100° C. for 1 h. After filtration and removal ofthe solvent, an oily residue was obtained as the desired product (70mg). The crude product was used directly in the next step withoutfurther purification. LCMS calcd for C₁₁H₁₁O₅ (M+H)⁺: m/z=223.1. Found:223.1.

Step 3: Methyl1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate

To a solution of methyl2,5-dioxo-5,6,7,8-tetrahydro-2n-chromene-3-carboxylate (30 mg, 0.14mmol) in tetrahydrofuran (0.4 mL) and N,N-dimethylformamide (0.1 mL) atrt was added p-fluoroaniline (15 mg, 0.14 mmol). The reaction mixturewas stirred at rt for 3 h, followed by the addition ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34 mg,0.18 mmol) and 4-dimethylaminopyridine (4.1 mg, 0.034 mmol) at rt. Thereaction mixture was stirred at rt for additional 20 h. Afterfiltration, the crude was purified by prep LC-MS (pH=2 method; WatersSunFire PrepC18 5 μm OBD™ column, 30×100 mm, 60 mL/min, eluting with agradient of MeCN and water with 0.1% TFA) to give the desired product(12 mg, 28%). LCMS calcd for C₁₇H₁₅FNO₄ (M+H)⁺: m/z=316.1. Found: 316.1.

Step 4:1-(4-Fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicAcid

To a solution of methyl1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate(5.0 mg, 0.016 mmol) in methanol (0.10 mL) was added 1.0 M sodiumhydroxide in water (0.15 mL). The reaction mixture was stirred at rt for30 min, and the crude was neutralized with HCl (1N), diluted with EtOAc.The EtOAc layer was separated, and the aqueous layer was washed withEtOAc twice. The combined organic layers were dried, concentrated undervacuum to give the desired acid product as off-white powders. LCMS calcdfor C₁₆H₁₃FNO₄ (M+H)⁺: m/z=302.1. Found: 302.2.

Step 5: 7-Vinylpyrrolo[2,1-f][1,2,4]triazin-4-amine

In a sealed flask a mixture of4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (from Aldrich, 1.52 g,9.86 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & WPharm Lab, 1.50 g, 7.04 mmol) and N,N-diisopropylethylamine (3.7 mL, 21mmol) in 1,4-dioxane (20 mL) and water (0.97 mL) was stirred and flushedwith N₂ for 5 min before bis(tri-t-butylphosphine)palladium (540 mg, 1.0mmol) was added. The reaction mixture was sealed and heated at 110° C.in an oil bath for 60 min, filtered through a pad of celite andconcentrated. The crude was purified by Biotage silica gel columnchromatography (40 g column, 0 to 100% EtOAc in hexanes) to give thedesired product as white powders (541 mg, 48%). LCMS calcd for C₈H₉N₄(M+H)⁺: m/z=161.1. Found: 161.1.

Step 6: 7-Ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 7-vinylpyrrolo[2,1-f][1,2,4]triazin-d-amine (1.00 g,6.24 mmol) in methanol (30 mL) was added a mixture of palladium (1.33 g)(5% Pd on carbon). The reaction mixture was placed on hydrogen Parrshaker at 25 psi for 2 h. After filtration through a celite pad, thefiltrate was concentrated under vacuum to give the desired product asoff-white powders. LCMS calcd for C₈H₁₁N₄ (M+H)⁺: m/z=163.1. Found:163.1.

Step 7: 5-Bromo-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (600 mg,3.7 mmol) in N,N-dimethylformamide (16 mL) was added N-bromosuccinimide(395 mg, 2.22 mmol). The resulting mixture was stirred at rt for 30 min,diluted with EtOAc and filtered. The filtrate was washed with saturatedNaHCO₃, water, dried over Na₂SO₄, filtered and concentrated under vacuumto give the desired product as tan solid. LCMS calcd for C₈H₁₀BrN₄(M+H)⁺: m/z=241.0, 243.0. Found: 241.0, 243.0.

Step 8: 5-(4-Aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine

In a sealed tube a mixture of5-bromo-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.83 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (from Aldrich,236 mg, 1.08 mmol) and N,N-diisopropylethylamine (0.43 mL, 2.5 mmol) in1,4-dioxane (3.24 mL) and water (0.30 mL) was stirred and flushed withN₂ for 5 min before bis(tri-t-butylphosphine)palladium (130 mg, 0.25mmol) was added. The reaction mixture was sealed and heated at 110° C.in an oil bath for 1 h. After filtration, the crude was diluted withMeOH and purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product as light brownpowders (88 mg, 42%). LCMS calcd for C₁₄H₁₆N₅ (M+H)⁺: m/z=254.1. Found:254.1.

Step 9:N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (3.2 mg,0.013 mmol),1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid (4.6 mg, 0.015 mmol) (prepared in Example 1, step 4),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (12 mg, 0.032 mmol) in N,N-dimethylformamide (0.10mL) and N,N-diisopropylethylamine (5.0 mg, 0.04 mmol) were mixedtogether and stirred at rt for 20 min. The mixture was filtered,concentrated and purified by prep LC-MS (pH=10 method; XBridge™ PrepC185 μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.15% NH₄OH) to give the desired product as white powders(1.6 mg, 20%). LCMS calcd for C₃₀H₂₆FN₆O₃ (M+H)⁺: m/z=537.2. Found:537.2.

Example 2.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:1-[(1R)-2-Hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylicAcid

Dimethyl [(2E)-3-methoxyprop-2-en-1-ylidene]malonate (from AcrosOrganics, 0.20 g, 1.00 mmol) was taken up in methanol (1.8 mL), combinedwith (2R)-2-amino-2-phenylethanol (0.14 g, 1.00 mmol) andN,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture wassealed and stirred for 2 h at 130° C. Then the reaction mixture wascombined with 2.0 M sodium hydroxide in methanol (5.0 mL) and 2.0 Msodium hydroxide in water (5.0 mL) and continuously stirred at rt for 2h. The crude was neutralized with HCl (3N), extracted with EtOAc×3. Thecombined organic layers were dried, filtered and concentrated undervacuum to give the desired product as light brown gum. LCMS calcd forC₁₄H₁₄NO₄ (M+H)⁺: m/z=260.1. Found: 260.1.

Step 2:N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-d-amine (3.0 mg,0.012 mmol) (prepared in Example HF1, step 8),1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylicacid (3.6 mg, 0.014 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (11.2 mg, 0.03 mmol) in N,N-dimethylformamide (0.10mL) and N,N-diisopropylethylamine (4.6 mg, 0.035 mmol) were mixedtogether and stirred at rt for 60 min. The reaction mixture wasfiltered, concentrated and purified by prep LC-MS (pH=10 method;XBridge™ PrepC18 5 μm OBD™ column, 30×100 mm, 60 mL/min, eluting with agradient of MeCN and water with 0.15% NH₄OH) to give the desired productas white powders (2.0 mg, 34%). LCMS calcd for C₂₈H₂₇N₆O₃ (M+H)⁺:m/z=495.2. Found: 495.2.

Example 3.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:1-[(1R)-2-Hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylicAcid

Dimethyl [(2E)-3-methoxyprop-2-en-1-ylidene]malonate (from AcrosOrganics, 200 mg, 1.00 mmol) was taken up in methanol (1.82 mL),combined with (R)-(−)-2-amino-1-propanol (from Aldrich, 75.0 mg, 1.00mmol) and N,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reactionmixture was sealed and stirred for 2 h at 130° C. Then the reactionmixture was combined with 2.0 M sodium hydroxide in methanol (5.0 mL)and 2.0 M sodium hydroxide in water (5.0 mL) and continuously stirred atrt for 2 h. The reaction mixture was acidified with 5.0 mL of HCl (3 N),concentrated under vacuum to remove solvents. The residue was washedwith THF and EtOAc, dried, filtered and concentrated under vacuum togive the desired product as off-white powders. LCMS calcd for C₉H₁₂NO₄(M+H)⁺: m/z=198.1. Found: 198.1.

Step 2:N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-d-amine (5.0 mg,0.020 mmol) (prepared in Example HF1, step 8),1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylicacid (4.7 mg, 0.024 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (18.8 mg, 0.05 mmol) in N,N-dimethylformamide (0.1mL) and N,N-diisopropylethylamine (7.7 mg, 0.06 mmol) were mixedtogether and stirred at rt for 30 min. The mixture was filtered,concentrated and purified by prep LC-MS (pH=10 method; XBridge™ PrepC185 μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.15% NH₄OH) to give the desired product as white powders(2.0 mg, 23%). LCMS calcd for C₂₃H₂₅N₆O₃ (M+H)⁺: m/z=433.2. Found:433.2.

Example 4.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:1-[(1R)-1-(Hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylicAcid

Dimethyl [(2E)-3-methoxyprop-2-en-1-ylidene]malonate (from AcrosOrganics, 200 mg, 1.00 mmol) was taken up in methanol (1.82 mL),combined with (2R)-2-aminobutan-1-ol (89.0 mg, 1.00 mmol) andN,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture wassealed and stirred for 2 h at 130° C. Then the reaction mixture wascombined with 2.0 M sodium hydroxide in methanol (5.0 mL) and 2.0 Msodium hydroxide in water (5.0 mL) and continuously stirred at rt for 1h. The reaction mixture was acidified with 5.0 mL of HCl (3 N),concentrated under vacuum to remove solvents. The residue was washedwith THF and EtOAc, dried, filtered and concentrated under vacuum togive the desired product as off-white powders. LCMS calcd for C₁₀H₁₄NO₄(M+H)⁺: m/z=212.1. Found: 212.1.

Step 2:N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-d-amine (5.0 mg,0.020 mmol) (prepared in Example HF1, step 8),1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylicacid (5.0 mg, 0.024 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (18.8 mg, 0.049 mmol) in N,N-dimethylformamide (0.1mL) and N,N-diisopropyl ethyl amine (7.7 mg, 0.06 mmol) were mixedtogether and stirred at rt for 30 min. The reaction mixture wasfiltered, concentrated and purified by prep LC-MS (pH=10 method;XBridge™ PrepC18 5 μm OBD™ column, 30×100 mm, 60 mL/min, eluting with agradient of MeCN and water with 0.15% NH₄OH) to give the desired productas white powders (1.7 mg, 19%). LCMS calcd for C₂₄H₂₇N₆O₃ (M+H)⁺:m/z=447.2. Found: 447.2.

Example 5.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (4.6 mg,0.02 mmol) (prepared in Example 1, step 8),l-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (from AurumPharmatech, 5 mg, 0.02 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (17.3 mg, 0.05 mmol) in N,N-dimethylformamide (0.1mL) and N,N-diisopropylethylamine (7 mg, 0.05 mmol) were mixed togetherand stirred at rt for 30 min. The reaction mixture was filtered,concentrated and purified by prep LC-MS (pH=10 method; XBridge™ PrepC185 μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.15% NH₄OH) to give the desired product as white powders(2.4 mg, 28%). LCMS calcd for C₂₇H₂₅N₆O₂ (M+H)⁺: m/z=465.2. Found:465.2.

Example 6.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (4 mg,0.02 mmol) (prepared in Example 1, step 8),1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (from Synthonix,2.9 mg, 0.02 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (12 mg, 0.03 mmol) in N,N-dimethylformamide (0.1 mL)and triethylamine (4.8 mg, 0.05 mmol) were mixed together and stirred atrt for 30 min. The reaction mixture was filtered, concentrated andpurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product as white powders (1.6 mg, 26%).LCMS calcd for C₂₁H₂₁N₆O₂ (M+H)⁺: m/z=389.2. Found: 389.2.

Example 7a.N-{4-[4-Amino-7-(cis-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideExample 7b.N-{4-[4-Amino-7-(trans-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: Methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate

A mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (fromAldrich, 1.50 g, 9.80 mmol), phenylboronic acid (3.6 g, 29 mmol),activated 4 Å molecular sieves (2.8 g, 12 mmol) and cupric acetate (3.6g, 20.0 mmol) in methylene chloride (60 mL) was treated with pyridine(2.4 mL, 29 mmol). The reaction mixture was stirred at rt for 60 h,filtered through a celite pad. The filtrate was concentrated undervacuum. The crude product was purified by Biotage silica gelchromatography (0 to 100% ethyl acetate in hexanes) to afford thedesired product as white powders (1.26 g, 56%). LCMS calcd for C₁₃H₁₂NO₃(M+H)⁺: m/z=230.1. Found: 230.1.

Step 2: 2-Oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic Acid

Methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (800 mg, 3.49mmol) was dissolved in tetrahydrofuran (7.4 mL) and methanol (3.7 mL).The mixture was then treated with 1.0 M sodium hydroxide in water (14.0mL), and stirred at rt for 30 min. The reaction mixture was neutralizedwith HCl (12 M) to pH=6-7. The solvents were removed under vacuum andthe product precipitated out. The solid was collected by vacuumfiltration, and the cake was washed with water and dried overnight togive the desired acid product as white powders (636 mg, 85%). LCMS calcdfor C₁₂H₁₀NO₃ (M+H)⁺: m/z=216.1. Found: 216.1.

Step 3:2-Oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(from Aldrich, 214 mg, 0.98 mmol) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.93 mmol) in N,N-dimethylformamide(4.5 mL) was added triethylamine (194 μL, 1.4 mmol) followed byN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (424 mg, 1.12 mmol). The resulting reaction mixture,which became a mixture of solids quickly, was stirred at rt for 1 h. Thesolids were filtered and washed with water. Drying by vacuum suctiongave the desired product as a white solid (306 mg, 79%). LCMS calcd forC₂₄H₂₆BN₂O₄ (M+H)⁺: m/z=417.2. Found: 417.2.

Step 4:7-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohex-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

A mixture oftert-butyl(dimethyl){[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]oxy}silane(450 mg, 1.33 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (283mg, 1.33 mmol), sodium carbonate (470 mg, 4.4 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (101mg, 0.133 mmol) in tert-butyl alcohol (4.0 mL) and water (1.5 mL) wasdegassed with nitrogen, then stirred and heated at 110° C. for 2 h, then95° C. overnight. The mixture was diluted with ethyl acetate, washedwith saturated NaHCO₃, water, dried over Na₂SO₄, filtered andconcentrated. The product was purified by Biotage silica gelchromatography (0 to 50% EtOAc in hexanes) to give the desired productas off-white powders (242.3 mg, 53%). LCMS calcd for C₁₈H₂₉N₄OSi (M+H)⁺:m/z=345.2. Found: 345.2.

Step 5:7-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohex-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(230 mg, 0.67 mmol) in methanol (2.8 mL) and tetrahydrofuran (1.4 mL)was added a mixture of palladium (4.6 mg) (10% Pd on carbon). Thereaction mixture was vacuumed and placed under a hydrogen balloon for 1h. After filtration through a celite pad, the filtrate was concentratedunder vacuum to give the desired product (161.9 mg, 70%). LCMS calcd forC₁₈H₃₁N₄OSi (M+H)⁺: m/z=347.2. Found: 347.2.

Step 6:5-Bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(80.0 mg, 0.23 mmol) in A, A-dimethylformamide (1.0 mL) was addedN-bromosuccinimide (39.0 mg, 0.22 mmol). The resulting mixture wasstirred at rt for 10 min. The reaction mixture was diluted with EtOAc,filtered. The filtrate was washed with saturated NaHCO₃, water, dried,filtered again and concentrated under vacuum to give the desired productas tan solid. LCMS calcd for C₁₈H₃₀BrN₄OSi (M+H)⁺: m/z=425.1, 427.1.Found: 425.1, 427.1.

Step 7:N-{4-[4-Amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A mixture of2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(48.9 mg, 0.12 mmol) (prepared in Example 7, step 3),5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(50 mg, 0.12 mmol), sodium carbonate (42 mg, 0.39 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (13.4mg, 0.018 mmol) in tert-butyl alcohol (0.35 mL) and water (0.13 mL) wasdegassed with nitrogen, then stirred and heated at 110° C. for 1 h. Themixture was diluted with ethyl acetate, washed with saturated NaHCO₃,water, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by Biotage silica gel chromatography (0 to 100% EtOAc inhexanes) to give the desired product as white powders (34 mg, 46%). LCMScalcd for C₃₆H₄₃N₆O₃Si (M+H)⁺: m/z=635.3. Found: 635.3.

Step 8:N-{4-[4-Amino-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A solution ofA-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(34 mg, 0.05 mmol) in tetrahydrofuran (0.2 mL) was treated with 4.0 Mhydrogen chloride in dioxane (0.9 mL, 3.6 mmol). The reaction mixturewas stirred at rt for 30 min. The crude (trans and cis isomers with aratio of 1:4) was concentrated under vacuum and purified by prep LC-MS(pH=10 method; XBridge™ PrepC18 5 μm OBD™ column, 30×100 mm, 60 mL/min,eluting with a gradient of MeCN and water with 0.15% NH₄OH) to give thedesired cis isomer (9.2 mg, 33%). The minor trans isomer (3.5 mg, 12%)was also isolated. Retention time (RT)=RT=1.189 min for minor transisomer, first peak off the column; RT=1.216 min for major cis isomer,second peak off the column. LCMS calcd for C₃₀H₂₉N₆O₃ (M+H)⁺: m/z=521.2.Found: 521.2. ¹H NMR (500 MHz, dmso) δ 12.06 (s, 1H), 8.62 (dd, J=7.3,2.2 Hz, 1H), 8.14 (dd, J=6.6, 2.2 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J=8.6Hz, 2H), 7.66-7.52 (m, 6H), 7.47 (d, J=8.5 Hz, 2H), 6.78-6.72 (m, 2H),6.55 (s, 1H), 4.38 (d, J=2.9 Hz, 1H), 3.92 (s, 1H), 3.62 (d, J=6.5 Hz,1H), 3.16 (t, J=11.4 Hz, 1H), 1.99-1.84 (m, 2H), 1.84-1.70 (m, 4H), 1.62(t, J=12.2 Hz, 1H).

Example 8.N-[4-(4-Amino-7-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: 7-Methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & WPharm Lab, 150 mg, 0.70 mmol) in tetrahydrofuran (2.86 mL) under N₂ atrt was added tetrakis(triphenylphosphine)palladium(0) (163 mg, 0.14mmol). The mixture in a sealed flask was evacuated and refilled with N₂several times, followed by the addition of 2.0 M dimethylzinc in toluene(5.3 mL, 10 mmol) at rt. The reaction mixture was heated at 90° C. for 4h. The reaction mixture was quenched with ice-water, extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered,concentrated under vacuum to give the crude, which was purified by prepLC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column, 30×100 mm, 60mL/min, eluting with a gradient of MeCN and water with 0.15% NH₄OH) toafford the desired product as white powders (29.2 mg, 28%). LCMS calcdfor C₇H₉N₄ (M+H)⁺: m/z=149.1. Found: 149.1.

Step 2: 5-Bromo-7-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 7-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (29.2 mg,0.20 mmol) in N,N-dimethylformamide (0.85 mL) was addedN-bromosuccinimide (33.3 mg, 0.19 mmol). The resulting mixture wasstirred at rt for 15 min and the reaction mixture was diluted withEtOAc, filtered, then washed with saturated NaHCO₃, water, dried,filtered and concentrated under vacuum to give the desired product asoff-white powders. LCMS calcd for C₇H₈BrN₄ (M+H)⁺: m/z=227.0, 229.0.Found: 227.0, 229.0.

Step 3:N-[4-(4-Amino-7-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (5.6 mg, 0.02mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(8.0 mg, 0.02 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.14 mL)and water (20 μL) was stirred together and flushed with N₂ bubble for 5min before bis(tri-t-butylphosphine)palladium (4.7 mg, 0.01 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (2.8 mg, 36%). LCMScalcd for C25H₂₁N₆O₂ (M+H)⁺: m/z=437.2. Found: 437.2.

Example 9.N-[4-(4-Amino-7-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1: Methyl1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

A mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (fromAldrich, 1.50 g, 9.8 mmol), 4-fluorophenylboronic acid (from Aldrich,4.1 g, 29 mmol), activated 4 Å molecular sieves (2.8 g, 12 mmol) andcupric acetate (3.6 g, 20 mmol) in methylene chloride (60 mL) wastreated with pyridine (2.4 mL) and then stirred at rt for 18 h. Themixture was filtered through celite and the filtrate was concentratedunder vacuum. The crude was purified by Biotage silica gel columnchromatography (0 to 100% ethyl acetate in hexanes) to afford thedesired product as off-white gum (1.33 g, 55%). LCMS calcd forC₁₃H₁₁FNO₃ (M+H)⁺: m/z=248.1. Found: 248.1.

Step 2: 1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic Acid

Methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (800mg, 3.24 mmol) was dissolved in tetrahydrofuran (6.82 mL) and methanol(3.41 mL). The mixture was then treated with 1.0 M sodium hydroxide inwater (12.9 mL), and the reaction mixture was stirred at rt for 30 min.The reaction mixture was neutralized with HCl (12 M) to pH=6-7. Thesolvents were removed under vacuum and the product precipitated out. Thesolid was collected by vacuum filtration, and the cake was washed withwater and dried overnight to give the desired acid product as whitepowders (540 mg, 72%). LCMS calcd for C₁₂H₉FNO₃ (M+H)⁺: m/z=234.1.Found: 234.1.

Step 3:1-(4-Fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(from Aldrich, 197.3 mg, 0.90 mmol) and1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (fromAldrich, 200 mg, 0.86 mmol) in NA-dimethylformamide (4.0 mL) was addedtriethylamine (180 μL, 1.3 mmol) followed byN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (391 mg, 1.03 mmol). The resulting mixture, whichbecame a mixture of solids quickly, was stirred at rt for 1 h. Thesolids were filtered and washed with water. Drying by vacuum suctiongave the desired product as a white solid (343 mg, 92%). LCMS calcd forC₂₄H₂₅BFN₂O₄ (M+H)⁺: m/z=435.2. Found: 435.2.

Step 4:N-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a mixture of3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (fromAldrich, 289.2 mg, 1.22 mmol) and2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (250 mg, 1.16 mmol)(prepared in Example 7, step 2) in N,N-dimethylformamide (5.0 mL) wasadded triethylamine (243 μL, 1.74 mmol) followed byN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (530 mg, 1.39 mmol). The resulting mixture, whichbecame a mixture of solids quickly, was stirred at rt for 1 h. Thesolids were filtered and washed with water. Drying by vacuum suctiongave the desired product as a white solid (335 mg, 66%). LCMS calcd forC₂₄H₂₅BFN₂O₄ (M+H)⁺: m/z=435.2. Found: 435.2.

Step 5:1-(4-Fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

To a mixture of3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (fromAldrich, 213.5 mg, 0.90 mmol) and1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg,0.86 mmol) (prepared in Example 9, step 2) in N A-dimethylformamide (4.7mL) was added triethylamine (179 μL, 1.29 mmol) followed byN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (391 mg, 1.03 mmol). The resulting mixture, whichbecame a mixture of solids quickly, was stirred at rt for 1 h. Thesolids were filtered and washed with water. Drying by vacuum suctiongave the desired product as a white solid (305 mg, 79%). LCMS calcd forC₂₄H₂₄BF₂N₂O₄ (M+H)⁺: m/z=453.2. Found: 453.2.

Step 6:N-[4-(4-Amino-7-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (5 mg, 0.02 mmol)(prepared in Example 8, step 2),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(8 mg, 0.02 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.01 mL, 0.05 mmol) in 1,4-dioxane (0.13 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.2 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (2.4 mg, 32%). LCMS calcd forC₂₅H₂₀FN₆O₂ (M+H)⁺: m/z=455.2. Found: 455.2.

Example 10.N-[4-(4-Amino-7-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (5 mg, 0.016 mmol)(prepared in Example 8, step 2),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(7.5 mg, 0.017 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.01 mL, 0.049 mmol) in 1,4-dioxane (0.128mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.2 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (1.7 mg, 23%). LCMS calcd forC₂₅H₂₀FN₆O₂ (M+H)⁺: m/z=455.2. Found: 455.2.

Example 11.N-[4-(4-Amino-7-methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (3.2 mg, 0.01 mmol)(prepared in Example 8, step 2),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(5 mg, 0.01 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.01 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.7 mg, 0.005 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (2.0 mg, 40%). LCMScalcd for C₂₅H₁₉F₂N₆O₂ (M+H)⁺: m/z=473.2. Found: 473.2.

Example 12.N-[4-(4-Amino-7-ethylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (6 mg, 0.018 mmol)(prepared in Example 1, step 7),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(8.3 mg, 0.02 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.02 mL, 0.11 mmol) in 1,4-dioxane (0.14 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.6 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (2.4 mg, 28%). LCMS calcd forC₂₆H₂₂FN₆O₂ (M+H)⁺: m/z=469.2. Found: 469.2.

Example 13.N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:7-(3,6-Dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

In a sealed flask a mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(from Aldrich, 0.64 g, 3.01 mmol),7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & W Pharm Lab, 0.500g, 2.35 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.0 mmol) in1,4-dioxane (6 mL) and water (0.32 mL) was stirred together and flushedwith N₂ for 5 min before bis(tri-t-butylphosphine)palladium (100 mg,0.24 mmol) was added. The reaction mixture was then sealed and heated at120° C. for 4 h, filtered through a pad of celite and concentrated. Thecrude was purified by Biotage silica gel column chromatography (40 gcolumn, 0 to 100% EtOAc in hexanes) to give the desired product as whitepowders (168.5 mg, 33%). LCMS calcd for C₁₁H₁₃N₄O (M+H)⁺: m/z=217.1.Found: 217.1.

Step 2: 7-(Tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (120mg, 0.55 mmol) in methanol (2.67 mL) and THF (1.3 mL) was added amixture of palladium (120 mg) (10% Pd on carbon). The reaction mixturewas placed under a hydrogen balloon for 2 hours. After filtrationthrough a celite pad, the filtrate was concentrated under vacuum to givethe desired product as white powders (90.2 mg, 75%). LCMS calcd forC₁₁H₁₅N₄O (M+H)⁺: m/z=219.1. Found: 219.1.

Step 3:5-Bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg,0.23 mmol) in N/V-dimethylformamide (0.99 mL) was addedN-bromosuccinimide (41 mg, 0.23 mmol). The resulting mixture was stirredat rt for 15 min. The reaction mixture was diluted with EtOAc, filtered.The filtrate was washed with saturated NaHCO₃, water, dried, filteredagain and concentrated under vacuum to give the desired product as tansolid. LCMS calcd for C₁₁H₁₄BrN₄O (M+H)⁺: m/z=297.0, 299.0. Found:297.0, 299.0.

Step 4:N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(8.8 mg, 0.02 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ or 5 minbefore bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (3.2 mg, 31%). LCMS calcd forC₂₉H₂₇N₆O₃ (M+H)⁺: m/z=507.2. Found: 507.2.

Example 14.N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol) (prepared in Example 13, step 3),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(9.2 mg, 0.02 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (4.8 mg, 45%). LCMS calcd forC₂₉H₂₆FN₆O₃ (M+H)⁺: m/z=525.2. Found: 525.2.

Example 15.N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(5 mg, 0.02 mmol) (prepared in Example 13, step 3),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(7.3 mg, 0.017 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.3 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 2 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN and waterwith 0.1% TFA) to give the desired product as white powders (6.4 mg,72%). LCMS calcd for C₂₉H₂₆FN₆O₃ (M+H)⁺: m/z=525.2. Found: 525.2.

Example 16.N-{4-[4-Amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol) (prepared in Example 13, step 3),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(9.6 mg, 0.02 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (4.4 mg, 40%). LCMS calcd forC₂₉H₂₅F₂N₆O₃ (M+H)⁺: m/z=543.2. Found: 543.2.

Example 17a.N-{4-[4-Amino-7-(cis-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideExample 17b.N-{4-[4-Amino-7-(trans-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:N-{4-[4-Amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(5 mg, 0.012 mmol) (prepared in Example 7, step 6),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(5.4 mg, 0.012 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.012 mL, 0.07 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3 mg, 0.006 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude wasused directly in the next step. LCMS calcd for C₃₆H₄₂FN₆O₃Si (M+H)⁺:m/z=653.3. Found: 653.3.

Step 2:N-{4-[4-Amino-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

A solution ofA-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(7.7 mg, 0.012 mmol) in methanol (0.05 mL) was treated with 4.0 Mhydrogen chloride in dioxane (0.20 mL). The reaction mixture was stirredat rt for 20 min. The crude was concentrated under vacuum and purifiedby prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column, 30×100mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15%NH₄OH) to give the desired product (cis isomer) as white powders (2.8mg, 44%). RT=2.047 min for the major cis isomer, second peak off thecolumn. The trans isomer is the minor product and is the first peak offthe column. The trans isomer was not isolated. LCMS calcd forC₃₀H₂₈FN₆O₃ (M+H)⁺: m/z=539.2. Found: 539.2.

Example 18a.N-{4-[4-Amino-7-(cis-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideExample 18b.N-{4-[4-Amino-7-(trans-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:N-{4-[4-Amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.014 mmol) (prepared in Example 7, step 6),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(6.1 mg, 0.014 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.014 mL, 0.08 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was directly used in the next step. LCMS calcd for C₃₆H₄₂FN₆O₃Si(M+H)⁺: m/z=653.3. Found: 653.3.

Step 2:N-{4-[4-Amino-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A solution ofN-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(9.2 mg, 0.014 mmol) in methanol (0.06 mL) was treated with 4.0 Mhydrogen chloride in dioxane (0.24 mL). The reaction mixture was stirredat rt for 30 min. The crude was concentrated under vacuum and purifiedby prep LC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.1% TFA) to give the desired product (cis isomer) as white powders.RT=1.208 min for the cis isomer, second peak off the column. LCMS calcdfor C₃₀H₂₈FN₆O₃ (M+H)⁺: m/z=539.2. Found: 539.2.

Example 19a.N-{4-[4-Amino-7-(cis-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideExample 19b.N-{4-[4-Amino-7-(trans-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:N-{4-[4-Amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(5 mg, 0.012 mmol) (prepared in Example 7, step 6),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(5.6 mg, 0.012 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.012 mL, 0.07 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3 mg, 0.006 mmol) was added.The reaction mixture was sealed and then heated at 100° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude wasused directly in the next step. LCMS calcd for C₃₆H₄₁F₂N₆O₃Si (M+H)⁺:m/z=671.3. Found: 671.3.

Step 2:N-{4-[4-Amino-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

A solution ofN-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(7.9 mg, 0.012 mmol) in methanol (0.05 mL) was treated with 4.0 Mhydrogen chloride in dioxane (0.2 mL). The reaction mixture was stirredat rt for 30 min. The crude was concentrated under vacuum and purifiedby prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column, 30×100mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.15%NH₄OH) to give the desired product (cis isomer) as white powders (1.8mg, 27%). RT=2.114 min for the major cis isomer, second peak off thecolumn. The trans isomer was not isolated, which is the first peak offthe column. LCMS calcd for C₃₀H₂₇F₂N₆O₃ (M+H)⁺: m/z=557.2. Found: 557.2.

Example 20.N-{4-[4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:7-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

The mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & WPharm Lab, 208 mg, 0.97 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(from Aldrich, 250 mg, 1.12 mmol), potassium phosphate (0.61 g, 2.9mmol) in 1,4-dioxane (3.4 mL) and water (1.1 mL) was degassed, refilledwith nitrogen, followed by addition ofdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (110 mg, 0.14 mmol). The reaction mixture was degassed again,refilled with nitrogen and was then sealed and heated at 80° C. for 1 h.The reaction mixture was allowed to cool to rt, diluted with ethylacetate, washed with brine, dried over sodium sulfate, filtered, andconcentrated under vacuum to give the crude product, which was useddirectly in the next step. LCMS calcd for C₁₂H₁₆N₅ (M+H)⁺: m/z=230.1.Found: 230.1.

Step 2: 7-(1-Methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(134 mg, 0.26 mmol) in methanol (1.26 mL) and THF (0.5 mL) was added amixture of palladium (150 mg, 0.14 mmol) (10% Pd on carbon). Thereaction mixture was placed under a hydrogen balloon for 4 hours. Afterfiltration through a celite pad, the filtrate was concentrated undervacuum to give the crude. The crude was further purified by prep LC-MS(pH=10 method; XBridge™ PrepC18 5 μm OBD™ column, 30×100 mm, 60 mL/min,eluting with a gradient of MeCN and water with 0.15% NH₄OH) to give thedesired product as white powders (22 mg, 36%). LCMS calcd for C₁₂H₁₈N₅(M+H)⁺: m/z=232.2. Found: 232.2.

Step 3:5-Bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (16.5 mg,0.07 mmol) in N,N-dimethylformamide (0.31 mL) and tetrahydrofuran (0.20mL) was added N-bromosuccinimide (10.2 mg, 0.06 mmol). The resultingmixture was stirred at rt for 10 min. The reaction mixture was dilutedwith EtOAc, filtered. The filtrate was washed with saturated NaHCO₃,water, dried, filtered and concentrated under vacuum to give the desiredproduct as tan solid. LCMS calcd for C₁₂H₁₇BrN₅ (M+H)⁺: m/z=310.1,312.1. Found: 310.1, 312.1.

Step 4:N-{4-[4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(4 mg, 0.013 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(5.6 mg, 0.014 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.012 mL, 0.078 mmol) in 1,4-dioxane (0.15 m)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (4.0 mg, 60%). LCMScalcd for C₃₀H₃₀N₇O₂ (M+H)⁺: m/z=520.2. Found: 520.2.

Example 21.N-{4-[4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(4 mg, 0.013 mmol) (prepared in Example 20, step 3),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(5.9 mg, 0.014 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.014 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (2.1 mg, 30%). LCMScalcd for C₃₀H₂₉FN₇O₂ (M+H)⁺: m/z=538.2. Found: 538.2.

Example 22.N-{4-[4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(3 mg, 0.01 mmol) (prepared in Example 20, step 3),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(4.2 mg, 0.01 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.01 mL, 0.03 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.5 mg, 0.005 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product. LCMS calcd forC₃₀H₂₉FN₇O₂ (M+H)⁺: m/z=538.2. Found: 538.2.

Example 23.N-{4-[4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(4 mg, 0.013 mmol) (prepared in Example 20, step 3),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(5.8 mg, 0.013 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.014 mL, 0.08 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (2.5 mg, 35%). LCMScalcd for C₃₀H₂₈F₂N₇O₂ (M+H)⁺: m/z=556.3. Found: 556.3.

Example 24.N-{4-[7-(1-Acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:7-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

A mixture of1-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(from Combi-Blocks, 500 mg, 1.99 mmol),7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & W Pharm Lab, 424mg, 1.99 mmol), sodium carbonate (700 mg, 6.6 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (199mg, 0.26 mmol) in tert-butyl alcohol (6.0 mL) and water (2.2 mL) wasdegassed with nitrogen, then stirred and heated at 110° C. for 2 h. Themixture was diluted with ethyl acetate, washed with saturated NaHCO₃,water, dried over Na₂SO₄, filtered and concentrated. The product waspurified by Biotage silica gel chromatography (20 g column, 0 to 30%MeOH in EtOAc) to give the desired product as brown solid (317 mg, 62%).LCMS calcd for C₁₃H₁₆N₅O (M+H)⁺: m/z=258.1. Found: 258.1.

Step 2: 7-(1-Acetylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a cloudy solution of7-(l-acetyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(305 mg, 1.19 mmol) in methanol (4.9 mL) and tetrahydrofuran (2.4 mL)was added a mixture of palladium (610 mg) (10% Pd on carbon). Thereaction mixture was placed under a hydrogen balloon for 18 h, andfiltered through a celite pad. The filtrate was concentrated undervacuum to give the desired product as light brown powders (187 mg, 61%).LCMS calcd for C₁₃H₁₈N₅O (M+H)⁺: m/z=260.1. Found: 260.1.

Step 3:7-(1-Acetylpiperidin-4-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(1-acetylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (178 mg,0.69 mmol) in N,N-dimethylformamide (3.0 mL) was addedN-bromosuccinimide (116 mg, 0.65 mmol). The resulting mixture wasstirred at rt for 15 min. The reaction mixture was diluted with EtOAc,and filtered. The filtrate was washed with saturated NaHCO₃, water,dried, filtered and concentrated under vacuum to give the desiredproduct as tan solid. LCMS calcd for C₁₃H₁₇BrN₅O (M+H)⁺: m/z=338.1,340.1. Found: 338.1, 340.1.

Step 4:N-{4-[7-(1-Acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of7-(1-acetylpiperidin-4-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(7.8 mg, 0.019 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.018 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.5 mg, 0.009 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (3.0 mg, 31%) as.LCMS calcd for C₃₁H₃₀N₇O₃ (M+H)⁺: m/z=548.2. Found: 548.2.

Example 25.N-{4-[7-(1-Acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of7-(1-acetylpiperidin-4-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol) (prepared in Example 24, step 3),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(8.1 mg, 0.019 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.018 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.5 mg, 0.009 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product (2.9 mg, 29%) as.LCMS calcd for C₃₁H₂₉FN₇O₃ (M+H)⁺: m/z=566.2. Found: 566.2.

Example 26.N-{4-[7-(1-Acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of7-(1-acetylpiperidin-4-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol) (prepared in Example 24, step 3),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(8.1 mg, 0.02 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.18 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.5 mg, 0.01 mmol) was added.The reaction mixture was sealed and then heated at 110° C. for 1 h.After separation and the aqueous layer extracted with EtOAc, the organiclayer was dried, filtered and concentrated under vacuum. The crude waspurified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μm OBD™ column,30×100 mm, 60 mL/min, eluting with a gradient of MeCN and water with0.15% NH₄OH) to give the desired product (2.4 mg, 24%) as. LCMS calcdfor C₃₁H₂₉FN₇O₃ (M+H)⁺: m/z=566.2. Found: 566.2.

Example 27.N-{4-[7-(1-Acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of7-(1-acetylpiperidin-4-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine(6 mg, 0.02 mmol) (prepared in Example 24, step 3),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(8.4 mg, 0.02 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.018 mL, 0.11 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (4.5 mg, 0.009 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired product as off-white powders(2.3 mg, 22%). LCMS calcd for C₃₁H₂₈F₂N₇O₃ (M+H)⁺: m/z=584.2. Found:584.2.

Example 28a.N-{4-[4-Amino-7-(cis-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideExample 28b.N-{4-[4-Amino-7-(trans-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohex-3-ene-1-carbonitrile

A mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carbonitrile(from Pharma Block, 500 mg, 2.15 mmol),7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & W Pharm Lab, 457mg, 2.14 mmol), sodium carbonate (760 mg, 7.1 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (211mg, 0.279 mmol) in tert-butyl alcohol (6.4 mL) and water (2.4 mL) wasdegassed with nitrogen, then stirred and heated at 110° C. for 2 h. Themixture was diluted with ethyl acetate, washed with saturated NaHCO₃,water, dried over Na₂SO₄, filtered and concentrated. The product waspurified by Biotage silica gel chromatography (20 g column, 0 to 100%EtOAc in hexanes) to give the desired product as off-white powders (238mg, 46%). LCMS calcd for C₁₃H₁₄N₅ (M+H)⁺: m/z=240.1. Found: 240.1.

Step 2:4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile

To a solution of4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohex-3-ene-1-carbonitrile(238 mg, 0.99 mmol) in methanol (4.1 mL) and tetrahydrofuran (2.0 mL)was added a mixture of palladium (512 mg) (10% Pd on carbon). Thereaction mixture was placed under a hydrogen balloon for 18 h. Afterfiltration through a celite pad, the filtrate was concentrated undervacuum to give the desired product as clear gum (147.2 mg, 61%). LCMScalcd for C₁₃H₁₆N₅ (M+H)⁺: m/z=242.1. Found: 242.1.

Step 3:4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile

To a solution of4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile (137mg, 0.57 mmol) in N,N-dimethylformamide (2.4 mL) was addedN-bromosuccinimide (96 mg, 0.54 mmol). The resulting mixture was stirredat rt for 15 min. The reaction mixture was diluted with EtOAc, andfiltered. The filtrate was washed with saturated NaHCO₃, water, dried,filtered and concentrated under vacuum to give the desired product asoff-white powders (182 mg, 100%). LCMS calcd for C₁₃H₁₅BrN₅ (M+H)⁺:m/z=320.0, 322.0. Found: 320.0, 322.0.

Step 4:N-{4-[4-Amino-7-(4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile(9 mg, 0.03 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(11.7 mg, 0.028 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.015 mL, 0.084 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ or 5 minbefore bis(tri-t-butylphosphine)palladium (7.2 mg, 0.014 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired cis isomer as off-whitepowders. RT=1.341 min for the cis isomer, first peak off the column.LCMS calcd for C₃₁H₂₈N₇O₂ (M+H)⁺: m/z=530.2. Found: 530.2.

Example 29a.N-{4-[4-Amino-7-(cis-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideExample 29b.N-{4-[4-Amino-7-(trans-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile(9 mg, 0.028 mmol) (prepared in Example 28, step 3),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(13 mg, 0.03 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.015 mL, 0.08 mmol) in 1,4-dioxane (0.11 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (7.2 mg, 0.014 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired cis isomer. RT=1.352 min forthe cis isomer, first peak off the column. LCMS (M+H)+: found m/z=548.3.LCMS calcd for C₃₁H₂₇FN₇O₂ (M+H)⁺: m/z=548.2. Found: 548.2.

Example 30a.N-{4-[4-Amino-7-(cis-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideExample 30b.N-{4-[4-Amino-7-(trans-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile(9 mg, 0.028 mmol) (prepared in Example 28, step 3),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(13 mg, 0.03 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.015 mL, 0.084 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (7.2 mg, 0.014 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 1h. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired cis isomer as white powders.RT=1.332 min for the cis isomer, first peak off the column. LCMS calcdfor C₃₁H₂₇FN₇O₂ (M+H)⁺: m/z=548.2. Found: 548.2.

Example 31a.N-{4-[4-Amino-7-(cis-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideExample 31b.N-{4-[4-Amino-7-(trans-4-cyanocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanecarbonitrile(9 mg, 0.03 mmol) (prepared in Example 28, step 3),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(13 mg, 0.03 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.015 mL, 0.084 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ bubblefor 5 min before bis(tri-t-butylphosphine)palladium (7.2 mg, 0.014 mmol)was added. The reaction mixture was sealed and then heated at 110° C.for 1 h. After separation and the aqueous layer extracted with EtOAc,the organic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=10 method; XBridge™ PrepC18 5 μmOBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCN andwater with 0.15% NH₄OH) to give the desired cis isomer as white powders.RT=2.666 min for the cis isomer, first peak off the column. LCMS (M+H)+:found m/z=566.3. LCMS calcd for C₃₁H₂₆F₂N₇O₂ (M+H)⁺: m/z=566.2. Found:566.2.

Example 32.N-[4-(4-Amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: tert-Butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(from Aldrich, 0.885 g, 2.86 mmol),7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & W Pharm Lab, 610mg, 2.86 mmol), sodium carbonate (1.0 g, 9.5 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (217mg, 0.286 mmol) in tert-butyl alcohol (8.6 mL) and water (3.2 mL) wasdegassed with nitrogen, then stirred and heated at 110° C. for 2 h. Themixture was diluted with ethyl acetate, washed with saturated NaHCO₃,water, dried over Na₂SO₄, filtered and concentrated. The crude waspurified by Biotage silica gel chromatography (40 g column, 0 to 100%EtOAc in hexanes) to give the desired product as off-white powders (705mg, 78%). LCMS calcd for C₁₆H₂₂N₅O₂ (M+H)⁺: m/z=316.2. Found: 316.2.

Step 2: tert-Butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a slightly cloudy solution of tert-butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 2.22 mmol) in methanol (9.2 mL) andtetrahydrofuran (4.6 mL) was added a mixture of palladium (2.20 g) (10%Pd on carbon). The reaction mixture was placed under a hydrogen balloonfor 20 h, and filtered through a celite pad. The filtrate wasconcentrated under vacuum to give the desired product as light brownpowders (455 mg, 65%). LCMS calcd for C₁₆H₂₄N₅O₂ (M+H)⁺: m/z=318.2.Found: 318.2.

Step 3: tert-Butyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(450 mg, 1.42 mmol) in N,N-dimethylformamide (6.1 mL) was addedN-bromosuccinimide (240 mg, 1.35 mmol). The resulting mixture wasstirred at rt for 10 min. The reaction mixture was diluted with EtOAc,filtered. The filtrate was washed with saturated NaHCO₃, water, dried,filtered and concentrated under vacuum to give the desired product astan solid. LCMS calcd for C₁₆H₂₃BrN₅O₂ (M+H)⁺: m/z=396.1, 398.1. Found:396.1, 398.1.

Step 4: 5-Bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amineDihydrochloride

tert-Butyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(562 mg, 1.42 mmol) was mixed with methanol (3.5 mL) and 4.0 M hydrogenchloride in dioxane (7.1 mL). The mixture was stirred at rt for 1 h.After concentration, the crude product was directly used in the nextstep as off-white powders. LCMS calcd for C₁₁H₁₅BrN₅ (M+H)⁺: m/z=296.0,298.0. Found: 296.0, 298.0.

Step 5:N-[4-(4-Amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (6.7 mg, 0.013 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(5.4 mg, 0.013 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.013 mL, 0.077 mmol) in 1,4-dioxane (0.15mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.0064 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 60min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (4 mg, 61%). LCMS calcd for C₂₉H₂₈N₇O₂ (M+H)⁺: m/z=506.2. Found:506.2.

Example 33.N-[4-(4-Amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(5.6 mg, 0.013 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.013 mL, 0.08 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 60min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as white powders (4mg, 59%). LCMS calcd for C₂₉H₂₇FN₇O₂ (M+H)⁺: m/z=524.2. Found: 524.2.

Example 34.N-[4-(4-Amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(5.6 mg, 0.013 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.0067 mL, 0.039 mmol) in 1,4-dioxane (0.15mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 60min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (3.2 mg, 47%). LCMS calcd for C₂₉H₂₇FN₇O₂ (M+H)⁺: m/z=524.2.Found: 524.2.

Example 35.N-[4-(4-Amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(5.8 mg, 0.013 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.014 mL, 0.077 mmol) in 1,4-dioxane (0.15mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.3 mg, 0.006 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 60min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as white powders(3.6 mg, 52%). LCMS calcd for C₂₉H₂₆F₂N₇O₂ (M+H)⁺: m/z=542.2. Found:542.2.

Example 36. Methyl4-[4-amino-5-(4-{[(2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

Step 1: Methyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) intetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water(0.65 mL, 0.65 mmol), followed by the slow addition of methylchloroformate (42 μL, 0.54 mmol) at 0° C. After stirred at rt for 10min, the resultant mixture was filtered, extracted with EtOAc, dried,filtered and concentrated to dryness under reduced pressure. Theresulting crude was used directly in the next step as light yellowpowders (52.6 mg). LCMS calcd for C₁₃H₁₇BrN₅O₂ (M+H)⁺: m/z=354.0, 356.0.Found: 354.0, 356.0.

Step 2: Methyl4-[4-amino-5-(4-{[(2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

In a sealed tube a mixture of methyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(6.8 mg, 0.014 mmol),2-oxo-1-phenyl-7V-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(6.2 mg, 0.015 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.0074 mL, 0.042 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (6.5 mg, 82%). LCMS calcd for C₃₁H₃₀N₇O₄ (M+H)⁺: m/z=564.2.Found: 564.2.

Example 37. Methyl4-{4-amino-5-[4-({[1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate

In a sealed tube a mixture of methyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(6.8 mg, 0.014 mmol) (prepared in Example 36, step 1),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(6.4 mg, 0.015 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.0074 mL, 0.042 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as off-white powders (5.0 mg, 61%). LC-MS foundm/z=582.3. LCMS calcd for C₃₁H₂₉FN₇O₄ (M+H)⁺: m/z=582.2. Found: 582.2.

Example 38. Methyl4-[4-amino-5-(2-fluoro-4-{[(2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

In a sealed tube a mixture of methyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(6.8 mg, 0.014 mmol) (prepared in Example 36, step 1),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(6.4 mg, 0.015 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.0074 mL, 0.04 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (6.4 mg, 78%). LCMS calcd forC₃₁H₂₉FN₇O₄ (M+H)⁺: m/z=582.2. Found: 582.2.

Example 39. Methyl4-{4-amino-5-[2-fluoro-4-({[1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate

In a sealed tube a mixture of methyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(6.8 mg, 0.014 mmol) (prepared in Example 36, step 1),1-(4-fluorophenyl)-TV-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(6.7 mg, 0.015 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.0074 mL, 0.042 mmol) in 1,4-dioxane (0.11mL) and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (4.9 mg, 58%). LCMS calcd forC₃₁H₂₈F₂N₇O₄ (M+H)⁺: m/z=600.2. Found: 600.2.

Example 40.N-(4-{4-Amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:5-Bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) intetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water(0.65 mL), followed by the slow addition of methanesulfonyl chloride (13μL, 0.16 mmol) at 0° C. After stirred at rt for 10 min, the resultantmixture was filtered, extracted with EtOAc, dried, filtered andconcentrated to dryness under reduced pressure. The resulting crude wasused directly in the next step as light yellow powders (36.5 mg, 90%).LCMS calcd for C₁₂H₁₇BrN₅O₂S (M+H)⁺: m/z=374.0, 376.0. Found: 374.0,376.0.

Step 2:N-(4-{4-Amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(5 mg, 0.01 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(5.8 mg, 0.014 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.4 mg, 0.0067 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (5.4 mg, 69%). LCMS calcd forC₃₀H₃₀N₇O₄S (M+H)⁺: m/z=584.2. Found: 584.2.

Example 41.N-(4-{4-Amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(5 mg, 0.013 mmol) (prepared in Example 40, step 1),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(6.1 mg, 0.014 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.4 mg, 0.0067 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (6.2 mg, 77%). LCMS calcd forC₃₀H₂₉FN₇O₄S (M+H)⁺: m/z=602.2. Found: 602.2.

Example 42.N-(4-{4-Amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(5 mg, 0.013 mmol) (prepared in Example 40, step 1),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(6.1 mg, 0.014 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.4 mg, 0.0067 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (3.8 mg, 47%). LCMS calcd forC₃₀H₂₉FN₇O₄S (M+H)⁺: m/z=602.2. Found: 602.2.

Example 43.N-(4-{4-Amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(5.3 mg, 0.014 mmol) (prepared in Example 40, step 1),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(6.7 mg, 0.015 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.01 mL, 0.05 mmol) in 1,4-dioxane (0.15 mL)and water (20 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (3.6 mg, 0.007 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 30min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (3.2 mg, 36%). LCMS calcd forC₃₀H₂₈F₂N₇O₄S (M+H)⁺: m/z=620.2. Found: 620.2.

Example 44.N-[4-(4-Amino-7-{1-[(dimethylamino)carbonyl]piperidin-4-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide

To a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) intetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water(0.65 mL, 0.65 mmol), followed by the slow addition ofN,N-dimethylcarbamoyl chloride (140 mg, 1.3 mmol) at 0° C. After stirredat rt for 80 min, the resultant mixture was filtered, extracted withEtOAc, dried, filtered and concentrated to dryness under reducedpressure. The resulting crude was used directly in the next step aslight yellow powders (59.8 mg). LCMS calcd for C₁₄H₂₀BrN₆O (M+H)⁺:m/z=367.1, 369.1. Found: 367.1, 369.1.

Step 2:N-[4-(4-Amino-7-{I-[(dimethylamino)carbonyl]piperidin-4-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide(3.8 mg, 0.007 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.1 mg, 0.0074 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 50min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as white powders (2mg, 49%). LCMS calcd for C₃₂H₃₃N₈O₃ (M+H)⁺: m/z=577.3. Found: 577.3.

Example 45.N-[4-(4-Amino-7-{1-[(dimethylamino)carbonyl]piperidin-4-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide(3.8 mg, 0.007 mmol) (prepared in Example 44, step 1),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.2 mg, 0.0074 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.006 mL, 0.03 mmol) in 1,4-dioxane (0.11 mL)and water (10 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 50min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (2.3 mg, 55%). LCMS calcd forC₃₂H₃₂FN₈O₃ (M+H)⁺: m/z=595.3. Found: 595.3.

Example 46.N-[4-(4-Amino-7-{1-[(dimethylamino)carbonyl]piperidin-4-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide(3.8 mg, 0.007 mmol) (prepared in Example 44, step 1),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(3.2 mg, 0.0074 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.006 mL, 0.03 mmol) in 1,4-dioxane (0.11 mL)and water (10 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 50min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (3.8 mg, 91%). LCMS calcd forC₃₂H₃₂FN₈O₃ (M+H)⁺: m/z=595.3. Found: 595.3.

Example 47.N-[4-(4-Amino-7-{1-[(dimethylamino)carbonyl]piperidin-4-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide(3.8 mg, 0.007 mmol) (prepared in Example 44, step 1),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(3.3 mg, 0.0074 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.006 mL, 0.03 mmol) in 1,4-dioxane (0.11 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 50min. The crude was diluted with MeOH, filtered and purified by prepLC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm,60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) togive the desired product as white powders (2.4 mg, 56%). LCMS calcd forC₃₂H₃₁F₂N₈O₃ (M+H)⁺: m/z=613.2. Found: 613.2.

Example 48.N-(4-{4-Amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:5-Bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (56 mg, 0.11 mmol) (prepared in Example 32, step 4) inethanol (0.5 mL) was added potassium carbonate (90 mg, 0.65 mmol),triethylamine (91 μL, 0.65 mmol) and potassium iodide (27 mg, 0.16mmol), followed by ethane, l-bromo-2-methoxy (75.4 mg, 0.54 mmol). Thereaction mixture was sealed and refluxed in an oil bath at 110° C. for 1h. After cooling, the mixture was filtered, and the cake was washed withEtOH. The filtrate was concentrated under reduced pressure to give thedesired product as off-white powders. LCMS calcd for C₁₄H₂₁BrN₅O (M+H)⁺:m/z=354.1, 356.1. Found: 354.1, 356.1.

Step 2:N-(4-{4-Amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(7.6 mg, 0.01 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.7 mg, 0.01 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.006 mL, 0.03 mmol) in 1,4-dioxane (0.1 mL)and water (10 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as white powders (4mg, 84%). LCMS calcd for C₃₂H₃₄N₇O₃ (M+H)⁺: m/z=564.3. Found: 564.3.

Example 49.N-(4-{4-Amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.9 mg, 0.01 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.1 mL)and water (10 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (3.2 mg, 65%). LCMS calcd for C₃₂H₃₃FN₇O₃ (M+H)⁺: m/z=582.3.Found: 582.3.

Example 50.N-(4-{4-Amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(3.9 mg, 0.01 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.007 mL, 0.03 mmol) in 1,4-dioxane (0.12 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (3.9 mg, 79%). LCMS calcd for C₃₂H₃₃FN₇O₃ (M+H)⁺: m/z=582.3.Found: 582.3.

Example 51.N-(4-{4-Amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine(7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(4.0 mg, 0.01 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 40min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as white powders(3.5 mg, 69%). LCMS calcd for C₃₂H₃₂F₂N₇O₃ (M+H)⁺: m/z=600.3. Found:600.3.

Example 52.N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:2-[4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol

To a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (56 mg, 0.11 mmol) in ethanol (0.5 mL) (prepared inExample 32, step 4) was added potassium carbonate (90 mg, 0.65 mmol),triethylamine (91 μL, 0.65 mmol) and potassium iodide (27 mg, 0.16mmol), followed by 2-bromoethanol (67.8 mg, 0.54 mmol). The reactionmixture was sealed and refluxed in an oil bath at 110° C. for 1 h. Aftercooling, the mixture was filtered, and the cake was washed with THF andEtOH. The filtrate was concentrated under reduced pressure to give thedesired product as off-white powders. LCMS calcd for C₁₂H₁₉BrN₅O (M+H)⁺:m/z=340.1, 342.1. Found: 340.1, 342.1.

Step 2:N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of2-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol(13 mg, 0.009 mmol),2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.7 mg, 0.01 mmol) (prepared in Example 7, step 3) andN,N-diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 20min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (2.3 mg, 49%). LCMS calcd for C₃₁H₃₂N₇O₃ (M+H)⁺: m/z=550.3.Found: 550.3.

Example 53.N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of2-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol(13 mg, 0.009 mmol) (prepared in Example 52, step 1),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.9 mg, 0.01 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.0042 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 20min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (2.3 mg, 48%). LCMS calcd for C₃₁H₃₁FN₇O₃ (M+H)⁺: m/z=568.2.Found: 568.2.

Example 54.N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of2-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol(13 mg, 0.009 mmol) (prepared in Example 52, step 1),N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(3.9 mg, 0.01 mmol) (prepared in Example 9, step 4) andN,N-diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.0042 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 20min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (2.7 mg, 56%). LCMS calcd for C₃₁H₃₁FN₇O₃ (M+H)⁺: m/z=568.2.Found: 568.2.

Example 55.N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of2-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol(13 mg, 0.009 mmol) (prepared in Example 52, step 1),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide(4.0 mg, 0.01 mmol) (prepared in Example 9, step 5) andN,N-diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL)and water (15 μL) was stirred together and flushed with N₂ for 5 minbefore bis(tri-t-butylphosphine)palladium (2.2 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110° C. for 20min. After separation and the aqueous layer extracted with EtOAc, theorganic layer was dried, filtered and concentrated under vacuum. Thecrude was purified by prep LC-MS (pH=2 method; Waters SunFire PrepC18 5μm OBD™ column, 30×100 mm, 60 mL/min, eluting with a gradient of MeCNand water with 0.1% TFA) to give the desired product as off-whitepowders (2.2 mg, 44%). LCMS calcd for C₃₁H₃₀F₂N₇O₃ (M+H)⁺: m/z=586.2.Found: 586.2.

Example 56.N-{4-[4-Amino-7-(1-{[ethyl(methyl)amino]carbonyl}piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-ethyl-N-methylpiperidine-1-carboxamide

To a mixture of5-bromo-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-aminedihydrochloride (20 mg, 0.04 mmol) (prepared in Example 32, step 4) intetrahydrofuran (0.2 mL) was added 1.0 M sodium bicarbonate in water(0.23 mL, 0.23 mmol), followed by the slow addition ofethyl(methyl)carbamic chloride (56.5 mg, 0.46 mmol) at 0 Celsius. Afterstirred at rt for 15 min, the resultant mixture was filtered, extractedwith EtOAc, dried, filtered and concentrated to dryness under reducedpressure. The resulting crude was used directly in the next step asoff-white powders (18.1 mg). LCMS calcd for C₁₅H₂₂BrN₆O (M+H)+:m/z=381.1, 383.1. Found: 381.0, 383.0.

Step 2:N-{4-[4-Amino-7-(1-{[ethyl(methyl)amino]carbonyl}piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-A-ethyl-N-methylpiperidine-1-carboxamide(3.3 mg, 0.007 mmol),1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(3.2 mg, 0.007 mmol) (prepared in Example 9, step 3) andN,N-diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL)and water (14 μL) was stirred together beforebis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. Thereaction mixture was sealed and then heated at 110 Celsius for 50 min.The crude was diluted with MeOH, filtered and purified by prep LC-MS(pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm, 60mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to givethe desired product as white powders (2.9 mg, 68%). LCMS calcd forC₃₃H₃₄FN₈O₃ (M+H)+: m/z=609.3. Found: 609.3.

Example 57.N-{4-[4-Amino-7-(1-{[ethyl(methyl)amino]carbonyl}piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Step 1:1-(4-Fluorophenyl)-2,5-dioxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(76.4 mg, 0.35 mmol) and1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid (100.0 mg, 0.33 mmol) (prepared in Example 1, step 4) inN,N-dimethylformamide (1.5 mL) was added triethylamine (69 μL, 0.5 mmol)followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (151 mg, 0.40 mmol). The resulting mixture, whichbecame a mixture of solids quickly, was stirred at rt for 60 min. Theprecipitate was filtered and washed with water and dry under vacuum toprovide the desired product as white powders (186 mg). LCMS calcd forC₂₈H₂₉BFN₂O₅ (M+H)+: m/z=503.1. Found: 503.1.

Step 2:N-{4-[4-Amino-7-(1-{[ethyl(methyl)amino]carbonyl}piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-A-ethyl-N-methylpiperidine-1-carboxamide(3.3 mg, 0.007 mmol) (prepared in Example 56, step 1),1-(4-fluorophenyl)-2,5-dioxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide(3.7 mg, 0.007 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.04 mmol)in 1,4-dioxane (0.10 mL) and water (14 μL) was stirred together beforebis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. Thereaction mixture was sealed and then heated at 110 Celsius for 50 min.The crude was diluted with MeOH, filtered and purified by prep LC-MS(pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm, 60mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to givethe desired product as white powders (3.8 mg, 80%). LCMS calcd forC₃₇H₃₈FN₈O₄ (M+H)+: m/z=677.3. Found: 677.3.

Example 58.N-{4-[4-Amino-7-(1-{[ethyl(methyl)amino]carbonyl}piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Step 1:1-(4-Fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

To a mixture of2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (82.6mg, 0.35 mmol) (from Combi-Block) and1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid (100.0 mg, 0.33 mmol) (prepared in Example 1, step 4) inN,N-dimethylformamide (1.5 mL) was added triethylamine (69 μL, 0.5 mmol)followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (151 mg, 0.40 mmol). The resulting mixture wasstirred at rt for 2 h. The reaction mixture was concentrated undervacuum to remove most solvents, and precipitated out. The precipitatewas filtered and washed with water. The cake was dried overnight byvacuum suction to give the desired product as off-white powders (156.5mg, 91%). LCMS calcd for C₂₈H₂₈BF₂N₂O₅ (M+H)+: m/z=521.1. Found: 521.1.

Step 2:N-{4-[4-Amino-7-(1-{[ethyl(methyl)amino]carbonyl}piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

In a sealed tube a mixture of4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-A-ethyl-N-methylpiperidine-1-carboxamide(3.3 mg, 0.007 mmol) (prepared in Example 56, step 1),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide(3.8 mg, 0.0074 mmol) and N,N-diisopropylethylamine (0.004 mL, 0.02mmol) in 1,4-dioxane (0.1 mL) and water (14 μL) was stirred togetherbefore bis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) wasadded. The reaction mixture was sealed and then heated at 110 Celsiusfor 50 min. The crude was diluted with MeOH, filtered and purified byprep LC-MS (pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100mm, 60 mL/min, eluting with a gradient of MeCN and water with 0.1% TFA)to give the desired product as white powders (1.9 mg, 39%). LCMS calcdfor C₃₇H₃₇F₂N₈O₄ (M+H)+: m/z=695.3. Found: 695.3.

Example 59.N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

In a sealed tube a mixture of2-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol(10 mg, 0.007 mmol) (prepared in Example 52, step 1),1-(4-fluorophenyl)-2,5-dioxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide(3.7 mg, 0.0074 mmol) (prepared in Example 57, step 1) andN,N-diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL)and water (14μ) was stirred together beforebis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. Thereaction mixture was sealed and then heated at 110 Celsius for 50 min.The crude was diluted with MeOH, filtered and purified by prep LC-MS(pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm, 60mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to givethe desired product as white powders (2.1 mg, 47%). LCMS calcd forC₃₅H₃₅FN₇O₄ (M+H)+: m/z=636.3. Found: 636.3.

Example 60.N-(4-{4-Amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-3-fluorophenyl)-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

In a sealed tube a mixture of2-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]ethanol(10 mg, 0.007 mmol) (prepared in Example 52, step 1),1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide(3.8 mg, 0.0074 mmol) (prepared in Example 58, step 1) andN,N-diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL)and water (14 μL) was stirred together beforebis(tri-t-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. Thereaction mixture was sealed and then heated at 110 Celsius for 50 min.The crude was diluted with MeOH, filtered and purified by prep LC-MS(pH=2 method; Waters SunFire PrepC18 5 μm OBD™ column, 30×100 mm, 60mL/min, eluting with a gradient of MeCN and water with 0.1% TFA) to givethe desired product as white powders (2.4 mg, 52%). LCMS calcd forC₃₅H₃₄F₂N₇O₄ (M+H)+: m/z=654.3. Found: 654.3.

Example 61.N-(4-(4-Amino-7-(1-(dimethylcarbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1: Diethyl 2-((3-phenylureido)methylene)malonate

To a mixture of diethyl (aminomethylene)malonate (6.0 g, 32 mmol) andphenyl isocyanate (3.8 mL, 35 mmol) in 1,2-dichloroethane (20 mL) at rtwas added N,N-diisopropylethylamine (7.2 mL, 42 mmol). The reactionmixture was then stirred at 70° C. overnight, cooled to rt, added Et₂O(50 mL), and stirred for another 30 min. The resulting solid wascollected by filtration, washed with ether, and dried to give theproduct as a white solid (4.88 g, 50%). LCMS calcd for C₁₅H₁₉N₂O₅(M+H)⁺: m/z=307.1. Found: 307.2.

Step 2: Ethyl2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of diethyl 2-((3-phenylureido)methylene)malonate from previousstep (4.88 g, 15.9 mmol) and 2.5 M NaOEt in EtOH (13 mL, 32 mmol) inEtOH (20 mL) was stirred at rt for 1 h. The resulting mixture wasdiluted with EtOAc, washed/acidified with 1 N citric acid, washed withwater, brine, dried over Na₂SO₄, and concentrated to provide the crudeproduct as a white solid, which was used directly in the next step (4.1g, 99%). LCMS calcd for C₁₃H₁₃N₂O₄ (M+H)⁺: m/z=261.1. Found: 261.1.

Step 3: ethyl1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of ethyl2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate fromprevious step (1.50 g, 5.76 mmol), isopropyl iodide (1.2 mL, 12 mmol),and Cs₂CO₃ (5.6 g, 17 mmol) in DMF (20 mL) was stirred at 50° C. for 5h. The reaction mixture was then cooled to rt, diluted with EtOAc,washed with water, brine, dried over Na₂SO₄, and concentrated to providethe crude product, which was used directly in the next step. LCMS calcdfor C₁₆H₁₉N₂O₄ (M+H)⁺: m/z=303.1. Found: 303.1.

Step 4:1-Isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

A mixture of ethyl1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom previous step (1.70 g, 5.62 mmol) in 4.0 M HCl in 1,4-dioxane (9.8mL, 39 mmol) and water (2.1 mL) was stirred at 60° C. for 4 h, cooled tort, and added water. The resulting solid was then collected byfiltration (washed with water) to give the product as a white solid (1.1g, 71%). LCMS calcd for C₁₄H₁₅N₂O₄ (M+H)⁺: m/z=275.1. Found: 275.1.

Step 5:1-Isopropyl-2,4-dioxo-3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture of1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid from previous step (400 mg, 1 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (320 mg, 1.46mmol) in DMF (8 mL) at rt was added Et₃N (305 μL, 2.19 mmol), followedby HATU (665 mg, 1.75 mmol). The resulting mixture was stirred at rt for2 h and added water. The resulting solid was collected by filtration,washed with water, and dried to give the product as a slightly yellowsolid (642 mg, 92%). LCMS calcd for C₂₆H₃₁BN₃O₅ (M+H)⁺: m/z=476.2.Found: 476.2.

Step 6: tert-Butyl4-[4-amino-5-(4-{[(1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

A mixture of1-isopropyl-2,4-dioxo-3-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamidefrom previous step (642 mg, 1.35 mmol), tert-butyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(535 mg, 1.35 mmol) (from example 32, step 3), XPhos Pd G2 (110 mg, 0.14mmol), and Na₂CO₃ (290 mg, 2.7 mmol) in 1,4-Dioxane (10 mL) and water(2.5 mL) was purged with nitrogen, and stirred at 70° C. for 2 h. Thereaction mixture was then cooled to rt, diluted with EtOAc, washed withwater, brine, dried over Na₂SO₄, concentrated, and purified via columnchromatography (0% to 12% MeOH in DCM) to give the crude product as ayellow solid, which was used directly in the next step (898 mg, 100%).LCMS calcd for C₃₆H₄₁N₈O₅ (M+H)⁺: m/z=665.3. Found: 665.3.

Step 7:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a solution of tert-butyl4-[4-amino-5-(4-{[(l-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylatefrom previous step (898 mg, 1.35 mmol) in CH₂Cl₂ (10 mL) at rt was added4.0 M HCl in 1,4-dioxane (3.4 mL, 14 mmol). The reaction mixture wasstirred at rt for 2 h, diluted with Et₂O, and the resulting solid wascollected by filtration to give the product as a yellow solid (˜2HClsalt) (702 mg, 81%). LCMS calcd for C₃₁H₃₃N₈O₃ (M+H)⁺: m/z=565.3. Found:565.3.

Step 8:N-(4-(4-Amino-7-(1-(dimethylcarbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a solution ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(2 HCl salt) from previous step (150 mg, 0.24 mmol) in CH₂Cl₂ (5.0 mL)at rt was added Et₃N (200 μL, 1.4 mmol), followed byN,N-dimethylcarbamoyl chloride (65 μL, 0.70 mmol). The reaction mixturewas stirred at rt for 3 h, diluted with CH₂Cl₂ (5.0 mL), washed withwater, dried over Na₂SO₄, and concentrated. The resulting residue wasdissolved in MeCN (5% water, 0.5% TFA), and purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as a whitesolid (TFA salt). LCMS calcd for C₃₄H₃₈N₉O₄ (M+H)⁺: m/z=636.3. Found:636.3. ¹H NMR (600 MHz, DMSO) δ 11.01 (s, 1H), 8.67 (s, 1H), 8.10 (s,1H), 7.80 (d, 7=8.7 Hz, 2H), 7.52 (td, J=6.9, 1.6 Hz, 2H), 7.49-7.43 (m,3H), 7.40-7.33 (m, 2H), 6.75 (s, 1H), 4.78 (hept, J=6.7 Hz, 1H), 3.66(d, J=13.1 Hz, 2H), 3.31 (tt, J=11.8, 3.5 Hz, 1H), 2.86 (t, J=11.7 Hz,2H), 2.75 (s, 6H), 1.97 (d, J=10.7 Hz, 2H), 1.67 (qd, J=12.6, 3.8 Hz,2H), 1.43 (d, J=6.8 Hz, 6H).

Example 62.N-(4-(4-Amino-7-(1-(ethyl(methyl)carbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a solution ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(2 HCl salt) (from example 61, step 7) (150 mg, 0.24 mmol) in CH₂Cl₂(5.0 mL) at rt was added Et₃N (200 μL, 1.4 mmol), followed byethyl(methyl)carbamic chloride (86 mg, 0.70 mmol). The reaction mixturewas stirred at rt overnight, diluted with CH₂Cl₂ (5.0 mL), washed withwater, dried over Na₂SO₄, and concentrated. The resulting residue wasdissolved in MeCN (5% water, 0.5% TFA), and purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as a whitesolid (TFA salt). LCMS calcd for C35H₄₀N₉O₄ (M+H)⁺: m/z=650.3. Found:650.3. ¹H NMR (600 MHz, DMSO) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.09 (s,1H), 7.79 (d, J=8.7 Hz, 2H), 7.56-7.50 (m, 2H), 7.50-7.43 (m, 3H),7.40-7.34 (m, 2H), 6.74 (s, 1H), 4.78 (p, J=6.8 Hz, 1H), 3.63 (d, J=13.0Hz, 2H), 3.30 (tt, J=11.8, 3.5 Hz, 1H), 3.12 (q, J=7.1 Hz, 2H), 2.85 (t,J=11.8 Hz, 2H), 2.74 (s, 3H), 1.97 (d, J=10.8 Hz, 2H), 1.67 (qd, J=12.6,3.7 Hz, 2H), 1.43 (d, J=6.8 Hz, 6H), 1.06 (t, J=7.1 Hz, 3H).

Example 63.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a solution ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(˜2HCl salt) (from example 61, step 7) (150 mg, 0.24 mmol) in CH₂Cl₂(5.0 mL) at rt was added Et₃N (200 μL, 1.4 mmol), followed by isobutyrylchloride (30 μL, 0.28 mmol). The reaction mixture was stirred at rt for15 min, diluted with CH₂Cl₂ (5.0 mL), washed with water, dried overNa₂SO₄, and concentrated. The resulting residue was dissolved in MeCN(5% water, 0.5% TFA), and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as a white solid (TFA salt).LCMS calcd for C₃₅H₃₉N₈O₄ (M+H)⁺: m/z=635.3. Found: 635.3. ¹H NMR (600MHz, DMSO) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.79 (d, J=8.7Hz, 2H), 7.54-7.50 (m, 2H), 7.49-7.43 (m, 3H), 7.39-7.34 (m, 2H), 6.72(s, 1H), 4.78 (p, J=6.8 Hz, 1H), 4.54 (d, J=12.4 Hz, 1H), 4.06 (d,J=12.6 Hz, 1H), 3.41 (tt, J=11.8, 3.6 Hz, 1H), 3.20 (t, J=12.5 Hz, 1H),2.90 (p, J=6.1 Hz, 1H), 2.69 (t, J=12.0 Hz, 1H), 2.03 (dd, J=31.6, 11.8Hz, 2H), 1.67-1.59 (m, 1H), 1.55-1.47 (m, 1H), 1.43 (d, J=6.8 Hz, 6H),1.05-0.97 (m, 6H).

Example 64.N-(4-(4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(˜2HCl salt) (from example 61, step 7) (150 mg, 0.24 mmol) in CH₂Cl₂ (10mL) at rt was added N,N-diisopropylethylamine (82 μL, 0.47 mmol). Theresulting mixture was stirred at rt for 15 min, and formaldehyde inwater (24 μL, 37 wt %, 0.30 mmol) was added to the mixture. Theresulting mixture was stirred for 15 min and NaBH(OAc)₃ (75 mg, 0.35mmol) was added to the mixture. The reaction mixture was then stirred atrt for 15 min, added water (2.25 mL), concentrated, dissolved in MeCN(5% water, 0.5% TFA), and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as a white solid (TFA salt).LCMS calcd for C₃₂H₃₅N₈O₃ (M+H)⁺: m/z=579.3. Found: 579.3. ¹H NMR (600MHz, DMSO) δ 10.99 (s, 1H), 8.67 (s, 1H), 7.99 (s, 1H), 7.79 (d, J=8.7Hz, 2H), 7.55-7.50 (m, 2H), 7.49-7.42 (m, 3H), 7.38-7.34 (m, 2H), 6.63(s, 1H), 4.79 (p, J=6.8 Hz, 1H), 3.54 (d, J=11.3 Hz, 2H), 3.41-3.34 (m,1H), 3.21-3.12 (m, 2H), 2.82 (d, J=4.6 Hz, 3H), 2.27 (d, J=13.9 Hz, 2H),1.93-1.84 (m, 2H), 1.43 (d, J=6.8 Hz, 6H).

Example 65.N-(4-(4-Amino-7-(1-(dimethylcarbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 61. LCMS calcd for C₃₄H₃₇FN₉O₄ (M+H)⁺: m/z=654.3.Found: 654.3. ¹H NMR (600 MHz, DMSO) δ 10.98 (s, 1H), 8.67 (s, 1H), 8.08(s, 1H), 7.83-7.75 (m, 2H), 7.48-7.45 (m, 2H), 7.45-7.41 (m, 2H),7.38-7.32 (m, 2H), 6.73 (s, 1H), 4.81-4.75 (m, 1H), 3.66 (d, J=13.1 Hz,2H), 3.34-3.27 (m, 1H), 2.86 (t, J=11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d,J=10.7 Hz, 2H), 1.71-1.63 (m, 2H), 1.43 (d, J=6.8 Hz, 6H).

Example 66.N-(4-(4-Amino-7-(1-(ethyl(methyl)carbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 62. LCMS calcd for C₃₅H₃₉FN₉O₄ (M+H)⁺: m/z=668.3.Found: 668.2. H NMR (600 MHz, DMSO) δ 10.98 (s, 1H), 8.67 (s, 1H), 8.07(s, 1H), 7.83-7.76 (m, 2H), 7.50-7.41 (m, 4H), 7.39-7.33 (m, 2H), 6.73(s, 1H), 4.82-4.73 (m, 1H), 3.63 (d, J=13.1 Hz, 2H), 3.34-3.25 (m, 1H),3.12 (q, J=7.1 Hz, 2H), 2.85 (t, J=11.7 Hz, 2H), 2.74 (s, 3H), 1.98 (d,J=10.6 Hz, 2H), 1.73-1.61 (m, 2H), 1.43 (d, J=6.8 Hz, 6H), 1.06 (t,J=7.1 Hz, 3H).

Example 67.N-(4-(4-Amino-7-(1-(dimethylcarbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 61. LCMS calcd for C₃₃H₃₅FN₉O₄ (M+H)⁺: m/z=640.3.Found: 640.3. ¹H NMR (600 MHz, DMSO) δ 10.97 (s, 1H), 8.87 (s, 1H), 8.09(s, 1H), 7.82-7.76 (m, 2H), 7.48-7.40 (m, 4H), 7.38-7.33 (m, 2H), 6.74(s, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.66 (d, J=13.1 Hz, 2H), 3.34-3.27 (m,1H), 2.86 (t, J=11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J=10.6 Hz, 2H),1.71-1.62 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

Example 68.N-(4-(4-Amino-7-(1-(morpholine-4-carbonyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 61. LCMS calcd for C₃₅H₃₇FN₉O₅ (M+H)⁺: m/z=682.3.Found: 682.3. ¹H NMR (600 MHz, DMSO) δ 10.97 (s, 1H), 8.86 (s, 1H), 8.08(s, 1H), 7.82-7.76 (m, 2H), 7.48-7.39 (m, 4H), 7.39-7.31 (m, 2H), 6.72(s, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.72 (d, J=13.1 Hz, 2H), 3.59-3.54 (m,4H), 3.37-3.28 (m, 1H), 3.16-3.11 (m, 4H), 2.92 (t, J=11.8 Hz, 2H), 1.98(d, J=10.7 Hz, 2H), 1.71-1.61 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

Example 69.N-(4-(4-Amino-7-(1-(ethyl(methyl)carbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(2-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 62. LCMS calcd for C₃₅H₃₉FN₉O₄ (M+H)⁺: m/z=668.3.Found: 668.3. ¹H NMR (600 MHz, DMSO) δ 10.83 (s, 1H), 8.72 (s, 1H), 8.07(s, 1H), 7.82-7.77 (m, 2H), 7.59-7.51 (m, 2H), 7.49-7.35 (m, 4H), 6.73(s, 1H), 4.81-4.73 (m, 1H), 3.63 (d, J=13.1 Hz, 2H), 3.34-3.26 (m, 1H),3.12 (q, J=7.1 Hz, 2H), 2.85 (t, J=11.7 Hz, 2H), 2.74 (s, 3H), 1.98 (d,J=10.6 Hz, 2H), 1.67 (qd, J=12.6, 3.7 Hz, 2H), 1.44 (d, J=6.8 Hz, 6H),1.06 (t, J=7.1 Hz, 3H).

Example 70.N-(4-(4-Amino-7-(1-(dimethylcarbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 61. LCMS calcd for C₃₄H₃₇FN₉O₄ (M+H)⁺: m/z=654.3.Found: 654.2. ¹H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.68 (s, 1H), 8.08(s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.63-7.52 (m, 1H), 7.47 (d, J=8.6 Hz,2H), 7.38-7.29 (m, 2H), 7.25 (d, J=8.2 Hz, 1H), 6.74 (s, 1H), 4.78 (p,J=6.8 Hz, 1H), 3.66 (d, J=13.0 Hz, 2H), 3.37-3.20 (m, 1H), 2.87 (q,J=11.3, 10.6 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J=10.8 Hz, 2H), 1.75-1.59(m, 2H), 1.43 (d, J=6.8 Hz, 6H).

Example 71.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 63. LCMS calcd for C₃₅H₃₅FN₈O₄ (M+H)⁺: m/z=653.3.Found: 653.3. ¹H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.68 (s, 1H), 8.06(s, 1H), 7.82-7.76 (m, 2H), 7.61-7.53 (m, 1H), 7.47-7.43 (m, 2H),7.36-7.30 (m, 2H), 7.27-7.22 (m, 1H), 6.72 (s, 1H), 4.78 (p, J=6.8 Hz,1H), 4.54 (d, J=12.2 Hz, 1H), 4.07 (d, J=12.8 Hz, 1H), 3.45-3.37 (m,1H), 3.20 (q, J=10.7, 8.7 Hz, 1H), 2.90 (dq, J=13.5, 6.7 Hz, 1H), 2.69(t, J=12.1 Hz, 1H), 2.03 (dd, J=31.3, 11.9 Hz, 2H), 1.67-1.47 (m, 2H),1.43 (d, J=6.8 Hz, 6H), 1.04-0.98 (m, 6H).

Example 72.N-(4-(4-Amino-7-(1-(dimethylcarbamoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 61. LCMS calcd for C₃₃H₃₅FN₉O₄ (M+H)⁺: m/z=640.3.Found: 640.3. ¹H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.88 (s, 1H), 8.07(s, 1H), 7.83-7.75 (m, 2H), 7.57 (ddd, J=9.0, 7.9, 6.4 Hz, 1H),7.49-7.43 (m, 2H), 7.36-7.31 (m, 2H), 7.25 (ddd, J=1.9, 1.7, 1.0 Hz,1H), 6.73 (s, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.66 (d, J=13.1 Hz, 2H),3.34-3.26 (m, 1H), 2.86 (t, J=11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d,J=10.7 Hz, 2H), 1.72-1.61 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

Example 73.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(3-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 63. LCMS calcd for C₃₄H₃₆FN₈O₄ (M+H)⁺: m/z=639.3.Found: 639.2. ¹H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.88 (s, 1H), 8.10(s, 1H), 7.84-7.73 (m, 2H), 7.60-7.52 (m, 1H), 7.49-7.43 (m, 2H),7.38-7.30 (m, 2H), 7.25 (ddd, J=1.9, 1.6, 1.0 Hz, 1H), 6.75 (s, 1H),4.54 (d, J=12.4 Hz, 1H), 4.11-3.97 (m, 3H), 3.41 (tt, J=11.8, 3.6 Hz,1H), 3.20 (t, J=12.3 Hz, 1H), 2.94-2.85 (m, 1H), 2.69 (t, J=12.0 Hz,1H), 2.03 (dd, J=31.1, 12.1 Hz, 2H), 1.69-1.45 (m, 2H), 1.30 (t, J=7.1Hz, 3H), 1.07-0.96 (m, 6H).

Example 74.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 57. LCMS calcd for C₃₇H₃₈N₇O₄ (M+H)⁺: m/z=644.3. Found:644.3. ¹H NMR (600 MHz, DMSO) δ 11.56 (s, 1H), 8.95 (s, 1H), 7.99 (s,1H), 7.87-7.77 (m, 2H), 7.69-7.61 (m, 2H), 7.60-7.56 (m, 1H), 7.50-7.39(m, 4H), 6.66 (s, 1H), 4.54 (d, J=11.9 Hz, 1H), 4.06 (d, J=13.0 Hz, 1H),3.44-3.36 (m, 1H), 3.25-3.14 (m, 1H), 2.95-2.86 (m, 1H), 2.73-2.65 (m,1H), 2.57-2.48 (m, 4H), 2.11-1.94 (m, 4H), 1.62 (d, J=8.8 Hz, 1H), 1.50(d, J=8.9 Hz, 1H), 1.01 (dd, J=9.9, 6.9 Hz, 6H).

Example 75.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)-3-fluorophenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 63, using3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline insteadof 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. This compoundwas purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as a white solid (TFA salt). LCMS calcd for C₃₅H₃₈FN₈O₄(M+H)⁺: m/z=653.3. Found: 653.3. ¹H NMR (400 MHz, DMSO) δ 11.10 (s, 1H),8.68 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J=12.4, 2.0 Hz, 1H), 7.52 (dd,J=8.1, 6.6 Hz, 2H), 7.49-7.43 (m, 2H), 7.41-7.32 (m, 3H), 6.68 (s, 1H),4.82-4.75 (m, 1H), 4.54 (d, J=13.2 Hz, 1H), 4.06 (d, J=13.0 Hz, 1H),3.45-3.37 (m, 1H), 3.20 (t, J=12.2 Hz, 1H), 2.90 (p, J=6.7 Hz, 1H),2.72-2.62 (m, 1H), 2.12-1.93 (m, 2H), 1.69-1.47 (m, 2H), 1.43 (d, J=6.8Hz, 6H), 1.01 (broad s, 6H).

Example 76.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(2,5-difluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 63, using 1,4-difluoro-2-isocyanatobenzene instead ofisocyanatobenzene. This compound was purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₅H₃₇F₂N₈O₄ (M+H)⁺: m/z=671.3. Found: 671.2. ¹H NMR (400 MHz, DMSO) δ10.76 (s, 1H), 8.73 (s, 1H), 8.04 (s, 1H), 7.81 (d, J=8.6 Hz, 2H),7.59-7.49 (m, 2H), 7.47 (d, J=8.6 Hz, 3H), 6.71 (s, 1H), 4.79 (p, J=6.8Hz, 1H), 4.55 (d, J=12.1 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.42 (t,J=11.8 Hz, 1H), 3.26-3.15 (m, 1H), 2.91 (p, J=6.7 Hz, 1H), 2.75-2.64 (m,1H), 2.11-1.96 (m, 2H), 1.58 (m, J=10.6 Hz, 2H), 1.45 (dd, J=6.7, 3.1Hz, 6H), 1.03 (d, J=5.5 Hz, 6H).

Example 77.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)-3-methylphenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 63, using3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline insteadof 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. This compoundwas purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as a white solid (TFA salt). LCMS calcd for C₃₆H₄₁N₈O₄(M+H)⁺: m/z=649.3. Found: 649.3.

Example 78.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 63, using 3-isocyanatopyridine instead ofisocyanatobenzene. This compound was purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as a white solid (TFA salt).LCMS calcd for C₃₄H₃₈N₉O₄ (M+H)⁺: m/z=636.3. Found: 636.3. ¹H NMR (500MHz, DMSO) δ 10.89 (s, 1H), 8.70 (s, 1H), 8.67 (dd, J=4.8, 1.4 Hz, 1H),8.60 (d, J=2.2 Hz, 1H), 8.09 (s, 1H), 7.92-7.86 (m, 1H), 7.80 (d, J=8.7Hz, 2H), 7.61 (dd, J=7.9, 4.6 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 6.75 (s,1H), 4.83-4.76 (m, 1H), 4.54 (d, J=11.9 Hz, 1H), 4.07 (d, J=12.0 Hz,1H), 3.46-3.36 (m, 1H), 3.20 (t, J=12.6 Hz, 1H), 2.90 (p, J=6.7 Hz, 1H),2.69 (t, J=11.7 Hz, 1H), 2.10-1.95 (m, 2H), 1.69-1.48 (m, 2H), 1.44 (d,J=6.8 Hz, 6H), 1.01 (t, J=6.8 Hz, 6H).

Example 79.(R)—N-(4-(4-Amino-7-(1-(2-hydroxypropanoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 61, from step 1 to step 7, using1-fluoro-4-isocyanatobenzene instead of isocyanatobenzene, and usingethyl iodide instead of isopropyl iodide. LCMS calcd for C₃₀H₃₀FN₈O₃(M+H)⁺: m/z=569.2. Found: 569.3.

Step 2:(R)—N-(4-(4-Amino-7-(1-(2-hydroxypropanoyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide(2 HCl) (50.0 mg, 0.088 mmol) and (R)-2-hydroxypropanoic acid (16 mg,0.18 mmol) in DMF (3 mL) was added HATU (70 mg, 0.18 mmol), followed byEt₃N (61 μM, 0.44 mmol). The reaction mixture was stirred at rt for 1 h,diluted with MeCN (with 5% water, 0.5% TFA), and purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as a whitesolid (TFA salt). LCMS calcd for C₃₃H₃₄FN₈O₅ (M+H)⁺: m/z=641.3. Found:641.3. ¹H NMR (500 MHz, DMSO) δ 10.95 (s, 1H), 8.85 (s, 1H), 8.05 (s,1H), 7.78 (d, J=8.6 Hz, 2H), 7.48-7.38 (m, 4H), 7.37-7.30 (m, 2H), 6.69(d, J=11.8 Hz, 1H), 4.53-4.40 (m, 1H), 4.10 (d, J=11.4 Hz, 1H), 4.01 (q,7.1 Hz, 2H), 3.46-3.37 (m, 2H), 3.17 (m, 1H), 2.75 (m, 1H), 2.02 (d,J=10.9 Hz, 2H), 1.50 (m, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.18 (d, J=6.3 Hz,3H).

Example 80.N-(4-(4-Amino-7-(1-(cyclopropanecarbonyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(2-hydroxypropyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1: Ethyl1-(2-(tert-butyldimethylsilyloxy)propyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of ethyl2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg,0.58 mmol) (from example 61, step 2),((1-bromopropan-2-yl)oxy)(tert-butyl)dimethylsilane (292 mg, 1.15 mmol),and CsCO₃ (563 mg, 1.73 mmol) in DMF (5 mL) was stirred at 100° C. for 5h. The reaction mixture was then cooled to rt, diluted with EtOAc,washed with water, brine, dried over Na₂SO₄, and concentrated to affordthe crude product, which was used directly in the next step. LCMS calcdfor C₂₂H₃₃N₂O₅Si (M+H)⁺: m/z=433.2. Found: 433.2.

Step 2:1-(2-Hydroxypropyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

A mixture of ethyl1-(2-((tert-butyldimethylsilyl)oxy)propyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate(249 mg, 0.58 mmol) in 4 M HCl in 1,4-dioxane (1.44 mL, 5.76 mmol) andwater (0.50 mL) was stirred at 70° C. for 3 h, cooled to rt, andconcentrated. The resulting material was then purified via pH 2preparative LC/MS (MeCN/water with TFA) to afford the product as ayellow oil, which was used directly in the next step. LCMS calcd forC₁₄H₁₅N₂O₅ (M+H)⁺: m/z=291.1. Found: 291.0.

Step 3:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(2-hydroxypropyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound (2 HCl salt) was prepared following a synthetic sequenceanalogous to that for example 61 from step 5 to step 7, using1-(2-hydroxypropyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid instead of1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. LCMS calcd for C₃₁H₃₃N₈O₄ (M+H)⁺: m/z=581.3. Found: 581.3.

Step 4:N-(4-(4-Amino-7-(1-(cyclopropanecarbonyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(2-hydroxypropyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture ofN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-(2-hydroxypropyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(2 HCl salt) (25 mg, 0.038 mmol), cyclopropanecarboxylic acid (3.4 μl,0.042 mmol), and HATU (29 mg, 0.077 mmol) in DMF (1.0 mL) at rt wasadded Et₃N (0.027 mL, 0.191 mmol). The reaction mixture was stirred atrt for 2 h, and the resulting mixture was directly purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as a whitesolid (a pair of enantiomers) (TFA salt). LCMS calcd for C₃₅H₃₇N₈O₅(M+H)⁺: m/z=649.3. Found: 649.3.

Example 81.N-(4-(4-Amino-7-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A mixture ofN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(2 HCl salt) (from example 61, step 7) (180 mg, 0.28 mmol),2-bromo-N,N-dimethylacetamide (94 mg, 0.57 mmol), and Et₃N (0.197 ml,1.41 mmol) in DMF (2.5 ml) was stirred at rt for 3 h. The reactionmixture was diluted with MeOH, and directly purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as a whitesolid (TFA salt). LCMS calcd for C₃₅H₄₀N₉O₄ (M+H)⁺: m/z=650.3. Found:650.3. ¹H NMR (600 MHz, DMSO) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.03 (s,1H), 7.80 (d, J=8.5 Hz, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.49-7.39 (m, 3H),7.37 (d, J=7.3 Hz, 2H), 6.66 (s, 1H), 4.82-4.72 (m, 1H), 4.28 (s, 2H),3.60 (d, J=11.6 Hz, 2H), 3.47-3.34 (m, 1H), 3.26-3.12 (m, 2H), 2.96 (s,3H), 2.92 (s, 3H), 2.31-2.22 (m, 2H), 2.12-2.01 (m, 2H), 1.43 (d, J=6.8Hz, 6H).

Example 82.N-(4-(4-Amino-7-(1-(1-methyl-2-oxopyrrolidin-3-yl)piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 81, using 3-bromo-1-methylpyrrolidin-2-one instead of2-bromo-N,N-dimethylacetamide, and the reaction mixture was heated at75° C. for 1 h instead of being stirred at rt for 3 h. This compound waspurified via pH 2 preparative LC/MS (MeCN/water with TFA) to give theproduct as a white solid (a pair of enantiomers) (TFA salt). LCMS calcdfor C₃₆H₄₀N₉O₄ (M+H)⁺: m/z=662.3. Found: 662.3.

Example 83.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1:1-(4-(4-Amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one

To a mixture of5-bromo-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (2 HCl)(939 mg, 2.54 mmol) (from example 32, step 4) in CH₂Cl₂ (25 ml) at rtwas added Et₃N (1.77 ml, 12.7 mmol). The reaction mixture was stirred atrt for 1 h, and added isobutyryl chloride (0.29 ml, 2.80 mmol). Thereaction mixture was then stirred at rt for 30 min, concentrated, andthe resulting material was purified via column chromatography (0% to 10%MeOH in CH₂Cl₂) to give the product as a yellow solid (602 mg, 65%).LCMS calcd for C₁₅H₂₁BrN₅O (M+H)⁺: m/z=366.1. Found: 366.1.

Step 2:1-(4-(4-Amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one

A mixture of1-(4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(400 mg, 1.09 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (251 mg, 1.15mmol), XPhos Pd G2 (86 mg, 0.11 mmol), and Na₂CO₃ (232 mg, 2.18 mmol) in1,4-dioxane (7.5 ml)/water (1.5 ml) was first purged with N₂, andstirred at 85° C. for 3 h. The reaction mixture was then cooled to rt,filtered through a pad of Celite (washed with EtOAc), concentrated, andpurified via column chromatography (0% to 10% MeOH in CH₂Cl₂) to givethe product as a yellow solid (398 mg, 96%). LCMS calcd for C₂₁H₂₇N₆O(M+H)⁺: m/z=379.2. Found: 379.2.

Step 3: Diethyl 2-((3-pyridin-2-ylureido)methylene)malonate

To a mixture of diethyl 2-(aminomethylene)malonate (3.0 g, 16.0 mmol)and 2-isocyanatopyridine (2.02 g, 16.8 mmol) in 1,2-dichloroethane (9.0mL) at rt was added N,N-diisopropylethylamine (3.6 mL, 20.8 mmol). Thereaction mixture was then stirred at 70° C. overnight, cooled to rt, anddirectly purified via column chromatography (0% to 15% MeOH in CH₂Cl₂)to give the product (3.18 g, 65%). LCMS calcd for C₁₄H₁₈N₃O₅ (M+H)⁺:m/z=308.1. Found: 308.1.

Step 4:1-Isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

A mixture of diethyl 2-((3-(pyridin-2-yl)ureido)methylene)malonate (3.18g, 10.4 mmol) and 2.5 M NaOEt in EtOH (6.2 mL, 15.5 mmol) in EtOH (25mL) was stirred at it for 3 h. The resulting mixture was diluted withEtOAc, and washed/acidified with 1 N citric acid solution (30 mL). Theorganic layer was separated, and the aqueous layer was further extractedwith 3:1 CHCl₃/isopropyl alcohol (30 mL×3). The combined organic layerswere dried over Na₂SO₄, and concentrated to provide the crude product,ethyl2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate,which was used directly in the next step. LCMS calcd for C₁₂H₁₂N₃O₄(M+H)⁺: m/z=262.1. Found: 262.2.

A mixture of crude ethyl2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom previous step, 2-iodopropane (2.06 mL, 20.7 mmol), and Cs₂CO₃ (10.1g, 31.0 mmol) in DMF (35 mL) was stirred at 70° C. for 3 h. The reactionmixture was then cooled to rt, diluted with 3:1 CHCl₃/isopropyl alcohol(75 mL), washed with water, brine, dried over Na₂SO₄, and concentratedto afford the crude product, ethyl1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate,which was used directly in the next step. LCMS calcd for C₁₅H₁₈N₃O₄(M+H)⁺: m/z=304.1. Found: 304.1.

A mixture of crude ethyl1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom previous step in 4 M HCl in 1,4-dioxane (20 mL, 82 mmol) and water(5.0 mL) was stirred at 80° C. for 5 h, cooled to rt, and concentrated.The resulting material was then purified via column chromatography (0%to 15% MeOH in CH₂Cl₂) to give the product as a slightly yellow solid(1.50 g, 47% three steps). LCMS calcd for C₁₃H₁₄N₃O₄ (M+H)⁺: m/z=276.1.Found: 276.1.

Step 5:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (85 mg, 0.31 mmol),1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(129 mg, 0.34 mmol), and HATU (141 mg, 0.37 mmol) in DMF (3.5 mL) at itwas added Et₃N (0.13 mL, 0.93 mmol). The reaction mixture was stirred atrt for 1 h, diluted with CH₂Cl₂, and washed with water. The organiclayer was separated, dried over Na₂SO₄, concentrated, and purified viacolumn chromatography (0% to 10% MeOH in CH₂Cl₂) to give the product,which was further purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as a white solid (TFA salt). LCMS calcd forC₃₄H₃₈N₉O₄ (M+H)⁺: m/z=636.3. Found: 636.3. ¹H NMR (600 MHz, DMSO) δ10.86 (s, 1H), 8.71 (s, 1H), 8.63 (ddd, 4.8, 1.8, 0.9 Hz, 1H), 8.10 (s,1H), 8.06 (td, J=7.7, 1.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.61-7.53 (m,2H), 7.46 (d, J=8.6 Hz, 2H), 6.76 (s, 1H), 4.77 (p, J=6.8 Hz, 1H), 4.54(d, J=12.2 Hz, 1H), 4.07 (d, J=13.0 Hz, 1H), 3.41 (tt, J=11.8, 3.5 Hz,1H), 3.20 (t, J=12.4 Hz, 1H), 2.90 (p, J=6.7 Hz, 1H), 2.69 (t, J=12.1Hz, 1H), 2.02 (dd, J=30.5, 12.4 Hz, 2H), 1.70-1.48 (m, 2H), 1.44 (d,J=6.8 Hz, 6H), 1.08-0.93 (m, 6H).

Example 84.N-(4-(4-Amino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1:7-(3,5-Dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

A mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (0.32 g, 1.50mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.425 g, 1.80 mmol), Na₂CO₃ (0.318 g, 3.0 mmol), and XPhos Pd G2 (0.118g, 0.150 mmol) in 1,4-dioxane (6.0 ml)/water (1.0 ml) was vacuumed andrefilled with N₂ twice and the reaction was stirred at 95° C. overnight.The reaction mixture was then cooled to rt, diluted with EtOAc, washedwith water, brine, dried over Na₂SO₄, concentrated, and purified viacolumn chromatography (0% to 10% MeOH in CH₂Cl₂) to give the crudeproduct as a yellow solid. LCMS calcd for C₁₁H₁₃N₆ (M+H)⁺: m/z=229.1.Found: 229.1.

Step 2:5-Bromo-7-(3,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine

NBS (0.18 g, 1.0 mmol) was added to a solution of7-(3,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(0.23 g, 1.0 mmol) in DMSO (1.0 ml)/MeCN (1.0 ml)/water (20 μL) at 0° C.and the mixture was warmed to rt and stirred for 1 h. Water was added tothe reaction mixture and the resulting solid was collected byfiltration, washed with water, and dried to provide the product. LCMScalcd for C₁₁H₁₂BrN₆ (M+H)⁺: m/z=307.0. Found: 307.0.

Step 3:N-(4-(4-Amino-7-(3,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A mixture of5-bromo-7-(3,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(0.123 g, 0.40 mmol),3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide(0.217 g, 0.440 mmol) (prepared following a synthetic sequence analogousto that for example 61, from step 1 to step 5, using1-fluoro-3-isocyanatobenzene instead of isocyanatobenzene), Na₂CO₃(0.085 g, 0.80 mmol) and XPhos Pd G2 (0.031 g, 0.040 mmol) in1,4-dioxane (2.0 ml)/water (0.4 ml) was vacuumed and refilled with N₂twice and the reaction mixture was stirred at 75° C. overnight. Theresulting mixture was cooled to rt, diluted with MeCN (with 5% water,0.5% TFA), filtered, and purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as a white solid (TFA salt). LCMS calcdfor C₃₁H₂₉FN₉O₃ (M+H)⁺: m/z=594.2. Found: 594.2.

Step 4:N-(4-(4-Amino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Methyl iodide (3.2 μl, 0.051 mmol) was added to a mixture ofN-(4-(4-amino-7-(3,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide(30.0 mg, 0.051 mmol) and Cs₂CO₃ (32.9 mg, 0.10 mmol) in DMF (1.0 ml) atrt and the reaction mixture was stirred at rt for 1 h. The reactionmixture was then diluted with MeCN (with 5% water, 0.5% TFA), filtered,and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as a white solid (TFA salt). LCMS calcd for C₃₂H₃₁FN₉O₃(M+H)⁺: m/z=608.3. Found: 608.3.

Example 85.N-(4-(4-amino-7-(6-(dimethylcarbamoyl)-4-methylpyridin-3-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1:5-(4-Amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)-N,N,4-trimethylpicolinamide

This compound was prepared following a synthetic sequence analogous tothat for example 84, from step 1 to step 2, usingN,N,4-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideinstead of3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS calcd for C₁₅H₁₆BrN₆O (M+H)⁺: m/z=375.1. Found: 375.0.

Step 2:N-(4-(4-Amino-7-(6-(dimethylcarbamoyl)-4-methylpyridin-3-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A mixture of1-isopropyl-2,4-dioxo-3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide(30 mg, 0.063 mmol) (from example 61, step 5),5-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N,4-trimethylpicolinamide(26 mg, 0.069 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2) (5.0 mg, 6.3 μmol), and Na₂CO₃ (13.4 mg, 0.13 mmol)in 1,4-dioxane (1.5 mL)/water (0.3 mL) was purged with N₂, and stirredat 70° C. for 2 h. The reaction mixture was cooled to rt, diluted withMeOH, filtered, and purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as a white solid (TFA salt). LCMS calcd forC₃₅H₃₄N₉O₄ (M+H)⁺: m/z=644.3. Found: 644.3.

Example 86.4-Amino-5-(4-(3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)-N,N-dimethylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

Step 1: 4-Aminopyrrolo[1,2-f][1,2,4]triazine-7-carbonitrile

N,N,N′,N′-Tetramethylethylenediamine (40 μL, 0.3 mmol), ZnCN (118 mg,1.0 mmol), Tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol)and (9,9-dimethyl-9n-xanthene-4,5-diyl)bis(diphenylphosphine) (46 mg,0.080 mmol) was added successively to a solution of7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (210 mg, 1.0 mmol) in DMF(2.0 mL) in a microwave vial. The vial was sealed, degassed three times,and stirred at 160° C. under microwave conditions for 8 min. Thereaction mixture was cooled to rt, filtered (washed with CH₂Cl₂), andconcentrated. The resulting material was washed with MeCN, and dried toprovide the crude product, which was used directly in the next step.LCMS calcd for C₇H₆N₅ (M+H)⁺: m/z=160.1. Found: 160.0.

Step 2: 4-Amino-5-bromopyrrolo[1,2-f][1,2,4]triazine-7-carbonitrile

NBS (0.117 g, 0.66 mmol) was added to a solution of4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile (0.10 g, 0.63 mmol)in DMSO (1.0 mL)/MeCN (0.6 mL)/water (0.08 mL) at 0° C. and the reactionmixture was stirred at this temperature for 2 h. Water was added and theresulting solid was collected by filtration, washed with water, anddried to provide the product. LCMS calcd for C₇H₅BrN₅ (M+H)⁺: m/z=238.0.Found: 238.0.

Step 3: 4-Amino-5-bromopyrrolo[1,2-f][1,2,4]triazine-7-carboxylic Acid

M HCl in water (0.4 mL) was added to a mixture of4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.2mmol) in 1,4-dioxane (0.4 mL). The reaction was stirred at 95° C. for 4h, cooled to rt, and concentrated to give the crude product, which wasused directly in the next step. LCMS calcd for C₇H₆BrN₄O₂ (M+H)⁺:m/z=257.0. Found: 257.0.

Step 4:4-Amino-5-bromo-N,N-dimethylpyrrol[1,2-f][1,2,4]triazine-7-carboxamide

2 M Dimethylamine in THF (0.38 mL, 0.75 mmol) was added to a mixture of4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (25 mg,0.097 mmol) and BOP (60 mg, 0.14 mmol) in DMF (1.0 mL), followed by Et₃N(50 μL, 0.36 mmol). The reaction mixture was stirred at rt for 3 h,diluted with EtOAc, washed with saturated NaHCO₃ solution, water, brine,dried over Na₂SO₄, and concentrated to give the product, which was useddirectly in the next step. LCMS calcd for C₉H_(n)BrN₅O (M+H)⁺:m/z=284.0. Found: 284.0.

Step 5:4-Amino-5-(4-(3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)-N,N-dimethylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

A mixture of3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(0.020 g, 0.040 mmol) (prepared following a synthetic sequence analogousto that for example 61, from step 1 to step 5, using1-fluoro-3-isocyanatobenzene instead of isocyanatobenzene),4-amino-5-bromo-N,N-dimethylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide(0.016 g, 0.057 mmol), Na₂CO₃ (9.0 mg, 0.085 mmol) and XPhos Pd G2 (3.3mg, 0.0042 mmol) in 1,4-dioxane (1.0 mL)/water (0.1 mL) was vacuumed andrefilled with N₂ and stirred at 75° C. for 5 h. The resulting mixturewas then cooled to rt, diluted with MeCN (with 5% water, 0.5% TFA),filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA)to give the product as a white solid (TFA salt). LCMS calcd forC₂₉H₂₈FN₈O₄ (M+H)⁺: m/z=571.2. Found: 571.1.

Example 87.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1. Diethyl2-((3-(1-methyl-1H-pyrazol-4-yl)ureido)methylene)malonate

A mixture of 1-methyl-1H-pyrazol-4-amine (0.097 g, 1.0 mmol) and1,1′-carbonyldiimidazole (0.178 g, 1.100 mmol) in DMSO (1 mL) wasstirred at rt for 1 h, then diethyl 2-(aminomethylene)malonate (0.187 g,1.00 mmol) was added to the solution. The reaction mixture was stirredat 80° C. overnight, cooled to rt, and directly purified via columnchromatography (0% to 100% EtOAc in hexanes) to afford the product(0.204 g, 66%). LCMS calcd for C₁₃H₁₉N₄O₅ (M+H)⁺: m/z=311.1. Found:311.2.

Step 2. Ethyl3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of 2.5 M NaOEt in EtOH (0.39 mL, 0.99 mmol) and diethyl2-((3-(1-methyl-1H-pyrazol-4-yl)ureido)methylene)malonate (0.204 g, 0.66mmol) in EtOH (2 mL) was stirred at rt for 3 h. The resulting mixturewas diluted with CH₂Cl₂, and acidified with 1 N HCl to pH˜7. The organiclayer was separated, and the aqueous layer was further extracted with10% MeOH in CH₂Cl₂. The combined organic layers were dried over Na₂SO₄,and concentrated to provide the crude product (0.172 g, 99%), which wasused directly in the next step. LCMS calcd for C₁₁H₁₃N₄O₄ (M+H)⁺:m/z=265.1. Found: 265.2.

Step 3. Ethyl1-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of ethyl3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(0.172 g, 0.65 mmol), 2-iodopropane (0.13 mL, 1.30 mmol), and Cs₂CO₃(0.636 g, 1.95 mmol) in DMF (2 mL) was stirred at 80° C. for 3 h. Thereaction mixture was then cooled to rt, and filtered (washed withCH₂Cl₂). The filtrate was diluted with 10% MeOH in CH₂Cl₂, washed withwater, brine, dried over Na₂SO₄, and concentrated to afford the crudeproduct (0.195 g, 98%), which was used directly in the next step. LCMScalcd for C₁₄H₁₉N₄O₄ (M+H)⁺: m/z=307.1. Found: 307.1.

Step 4.1-Isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

A mixture of ethyl1-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(0.195 g, 0.64 mmol) in 4 M HCl in dioxane (1.27 mL) and water (0.32 mL)was stirred at 80° C. overnight. The reaction mixture was then cooled tort, diluted with water (3 mL), and neutralized with 1N NaOH solution topH 5. The resulting mixture was extracted with 10% MeOH in CH₂Cl₂ (3mL×3), and the combined organic layers were dried over Na₂SO₄, andconcentrated to afford the crude product (0.172 g, 97%) which was useddirectly in the next step. LCMS calcd for C₁₂H₁₅N₄O₄ (M+H)⁺: m/z=279.1.Found: 279.1.

Step 5.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture of1-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL)was added1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(0.019 g, 0.050 mmol) (from example 83, step 2) and Et₃N (0.021 ml, 0.15mmol). The mixture was stirred at rt for 2 h., diluted with MeOH,adjusted with TFA to pH 2, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₃H₃₉N₁₀O₄ (M+H)⁺: m/z=639.3. Found: 639.3.

Example 88.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-3-(1-methyl-1H-pyrazol-3-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 1-methyl-1H-pyrazol-3-amine instead of1-methyl-1H-pyrazol-4-amine. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₃H₃₉N₁₀O₄ (M+H)⁺: m/z=639.3. Found: 639.3.

Example 89.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-3-(2-methylthiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 2-methylthiazol-5-amine instead of1-methyl-1H-pyrazol-4-amine. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₃H₃₈N₉O₄S (M+H)⁺: m/z=656.3. Found: 656.3.

Example 90.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-cyclohexyl-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1:3-Cyclohexyl-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

This compound was prepared following a synthetic sequence analogous tothat for example 61, step 1 to step 4, using isocyanatocyclohexaneinstead of isocyanatobenzene. LCMS calcd for C₁₄H₂₁N₂O₄ (M+H)⁺:m/z=281.2. Found: 281.1.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-cyclohexyl-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture of3-cyclohexyl-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL)was added1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(0.019 g, 0.050 mmol) (from example 83, step 2) and Et₃N (0.021 ml, 0.15mmol). The mixture was stirred at rt for 2 h., diluted with MeOH,adjusted with TFA to pH 2, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₅H₄₅N₈O₄ (M+H)⁺: m/z=641.4. Found: 641.3.

Example 91.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(3-cyanophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1:3-(3-Bromophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

This compound was prepared following a synthetic sequence analogous tothat for example 61, from step 1 to step 4, using1-bromo-3-isocyanatobenzene instead of isocyanatobenzene. LCMS calcd forC₁₄H₁₄BrN₂O₄ (M+H)⁺: m/z=353.0. Found: 353.1.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(3-bromophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture of3-(3-bromophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.018 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL)was added1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(0.019 g, 0.050 mmol) (from example 83, step 2) and Et₃N (0.021 ml,0.150 mmol). The mixture was stirred at rt for 2 h, and water (4 mL) wasadded. The resulting solid was collected by filtration, washed withwater, and dried to afford the product. LCMS calcd for C₃₅H₃₈BrN₈O₄(M+H)⁺: m/z=713.2. Found: 713.2.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(3-cyanophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(3-bromophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide(0.036 g, 0.050 mmol), potassium hexacyanoferrate(II) trihydrate (10.5mg, 0.025 mmol), tBuXPhos Pd G3 (0.32 mg, 0.40 μmol) and KOAc (0.61 mg,6.3 μmol) in a sealed screw vial was de-gassed and recharged with N₂.1,4-dioxane (0.50 mL) and water (0.50 mL) was then added. The mixturewas re-degassed and charged with N₂ for three cycles. The reactionmixture was then heated at 100° C. for 1 h, cooled to rt, diluted withMeOH, adjusted with TFA to pH 2, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₆H₃₈N₉O₄ (M+H)⁺: m/z=660.3. Found: 660.3.

Example 92.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-3-(5-methylisoxazol-3-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 5-methylisoxazol-3-amine instead of1-methyl-1H-pyrazol-4-amine. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₃H₃₈N₉O₅ (M+H)⁺: m/z=640.3. Found: 640.3.

Example 93.N-(4-(4-Amino-7-(4-(dimethylamino)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1: tert-Butyl(4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohex-3-en-1-yl)carbamate

In a sealed vial, a mixture of7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (300 mg, 1.41 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enylcarbamate(550 mg, 1.69 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (55.4 mg, 0.070 mmol) and potassium phosphate tribasic(0.35 ml, 4.22 mmol) in 1,4-dioxane (10 ml)/water (2.0 ml) was degassedand stirred at 90° C. under N₂ for 2.5 h. The reaction mixture wascooled to rt, diluted with EtOAc, and washed with brine. The organiclayer was separated, dried over Na₂SO₄, concentrated, and purified bycolumn chromatography (0% to 10% MeOH in CH₂Cl₂) to give the product(400 mg, 86%). LCMS calcd for C₁₇H₂₄N₅O₂ (M+H)⁺: m/z=330.2; Found:330.1.

Step 2: tert-Butyl(4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)carbamate

To a mixture of tert-butyl(4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohex-3-en-1-yl)carbamate(460 mg, 1.40 mmol) in MeOH (25 ml) was added 10% Pd/C (297 mg). Theresulting mixture was stirred under 1 atm H₂ (balloon). After 22 h, more10% Pd/C (160 mg) was added along with CH₂Cl₂ (5 mL). The reactionmixture was then stirred for another 23 h, filtered through Celite(washed with CH₂Cl₂), and concentrated to give the crude product (463mg), which was used directly in the next step. LCMS calcd for C₁₇H₂₆N₅O₂(M+H)⁺: m/z=332.2; Found: 332.2.

Step 3: tert-Butyl(4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)carbamate

To a solution of tert-butyl(4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)carbamate (463mg, 1.40 mmol) in DMF (15 ml) was added NBS (249 mg, 1.40 mmol). Theresulting mixture was stirred at rt overnight. Water was then added tothe reaction mixture, and the resulting solid was collected byfiltration, washed with water, and dried to give the product as a yellowsolid (443 mg), which was used directly in the next step. LCMS calcd forC₁₇H₂₅BrN₅O₂ (M+H)⁺: m/z=410.1; Found: 410.1.

Step 4:N-(4-(4-Amino-7-(4-aminocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A mixture of tert-butyl(4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl)carbamate(27.0 mg, 0.066 mmol),1-isopropyl-2,4-dioxo-3-phenyl-/V-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide(40.7 mg, 0.086 mmol) (from example 61, step 5),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (2.6 mg, 3.3 μmol) and potassium phosphate tribasic (41.9mg, 0.197 mmol) in 1,4-dioxane (0.50 mL)/water (0.10 mL) was stirred at90° C. under N₂ for 2 h, cooled to rt, and partitioned between CH₂Cl₂and water. The organic layer was separated and concentrated. To thecrude residue was added CH₂Cl₂ (400 uL) and TFA (200 μL). The resultingsolution was stirred at rt for 1 h, and concentrated. The crude materialwas purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as TFA salt. LCMS calcd for C₃₂H₃₅N₈O₃ (M+H)⁺: m/z=579.3;Found: 579.2.

Step 5:N-(4-(4-Amino-7-(4-(dimethylamino)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture ofN-(4-(4-amino-7-(4-aminocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(15 mg, 0.022 mmol), formaldehyde in water (37 wt %, 1.6 μL, 0.022 mmol)and Et₃N (12 μL, 0.087 mmol) in THF (0.30 ml) was added sodiumtriacetoxyborohydride (50 mg, 2.05 mmol). The resulting mixture wasstirred at rt overnight, filtered, and concentrated. The crude materialwas purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as TFA salt. LCMS calculated for C₃₄H₃₉N₈O₃ (M+H)⁺:m/z=607.3; Found: 607.3.

Example 94.N-(4-(4-amino-7-(1-(cyclopropanecarbonyl)azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1: 7-Iodopyrrolo[1,2-f][1,2,4]triazin-4-amine

N-Iodosuccinimide (2.5 g, 11 mmol) was added to a solution ofpyrrolo[1,2-f][1,2,4]triazin-4-amine (1.5 g, 11 mmol) in DMF (10 mL) atit and the reaction was stirred for 2 h. The reaction mixture was thendiluted with EtOAc, washed with water and concentrated. The resultingsolid was washed with water, and dried to give the product. LCMS calcdfor C₆H₆IN₄ (M+H)⁺: m/z=261.0. Found: 261.2.

Step 2: tert-Butyl3-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate

Zinc (0.690 g, 10.5 mmol) was suspended with 1,2-dibromoethane (60 μL,0.70 mmol) in DMF (20 mL). The resulting mixture was stirred at 70° C.for 10 min and cooled to rt. Chlorotrimethylsilane (89 μL, 0.70 mmol)was added and stirring was continued for 1 h. A solution of tert-butyl3-iodoazetidine-1-carboxylate (2.5 g, 8.8 mmol) in DMF (10 mL) was thenadded and the mixture was stirred at 40° C. for 1 h before a mixture of7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine (2.4 g, 9.2 mmol),Tris(dibenzylideneacetone)dipalladium(0) (0.80 g, 0.88 mmol) andTri-(2-furyl)phosphine (0.41 g, 1.8 mmol) in DMF (12 mL) was added. Thereaction mixture was then stirred at 75° C. overnight, cooled to rt, andpartitioned between EtOAc and saturated NH₄Cl solution. The organiclayer was separated, washed with water, dried over MgSO₄, concentratedand purified via column chromatography (0% to 100% EtOAc in hexanes) togive the product (1.0 g, 39%). LCMS calcd for C₁₄H₂₀N₅O₂ (M+H)⁺:m/z=290.2. Found: 290.2.

Step 3: tert-Butyl3-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate

NBS (0.55 g, 3.1 mmol) was added to a solution of tert-butyl3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate(0.94 g, 3.2 mmol) in DMSO/MeCN/water (7.0 mL/3.0 mL/0.2 mL) at 0° C.and the reaction mixture was stirred at this temperature for 2 h. Theresulting mixture was diluted with EtOAc, washed with water,concentrated, and purified via column chromatography (0% to 100% EtOAcin hexanes) to give the desire product (0.35 g, 29%). LCMS calcd forC₁₄H₁₉BrN₅O₂ (M+H)⁺: m/z=368.1. Found: 368.0.

Step 4: Tert-Butyl3-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.21 g, 0.95 mmol), tert-butyl3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate(0.35 g, 0.95 mmol), Cs₂CO₃ (0.62 g, 1.9 mmol) anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.075 g, 0.095 mmol) in 1,4-dioxane/water was stirred at 85° C.for 2 h. The reaction mixture was then cooled to rt, and purified viacolumn chromatography (0% to 100% EtOAc in hexanes) to give the product(0.28 g, 77%). LCMS calcd for C₂₀H₂₅N₆O₂ (M+H)⁺: m/z=381.2. Found:381.3.

Step 5: tert-butyl3-(4-amino-5-(4-(1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate

To a mixture of tert-butyl3-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]azetidine-1-carboxylate(140 mg, 0.37 mmol) and1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (110 mg, 0.40 mmol) (from example 61, step 4) in DMF (3.0 mL) wasadded Et₃N (0.10 mL, 0.74 mmol) followed by HATU (0.17 g, 0.44 mmol).The reaction mixture was stirred at rt for 1 h, quenched with water, andthe resulting solid was collected by filtration, and dried to give theproduct. LCMS calcd for C₃₄H₃₇N₈O₅ (M+H)⁺: m/z=637.3. Found: 637.2.

Step 6:N-(4-(4-Amino-7-(azetidin-3-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

tert-Butyl3-(4-amino-5-(4-(l-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)azetidine-1-carboxylate(0.25 g, 0.39 mmol) was treated with 4 M HCl in 1,4-dioxane (0.098 mL,0.39 mmol) in CH₂Cl₂ (1 mL) at rt for 1 h. The reaction mixture was thenconcentrated to give the product. LCMS calcd for C₂₉H₂₉N₈O₃ (M+H)⁺:m/z=537.2. Found: 537.2.

Step 7:N-(4-(4-Amino-7-(1-(cyclopropanecarbonyl)azetidin-3-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture ofN-(4-(4-amino-7-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(0.0055 g, 10.3 μmol) and Et₃N (2.86 μl, 0.020 mmol) in CH₂Cl₂ (1 ml)was added cyclopropanecarbonyl chloride (1.3 mg, 0.012 mmol). Thereaction mixture was stirred at rt for 1 h, concentrated, and purifiedvia pH 2 preparative LC/MS (MeCN/water with TFA) to give the product asTFA salt. LCMS calcd for C₃₃H₃₃N₈O₄ (M+H)⁺: m/z=605.3. Found: 605.2.

Example 95.N-(4-(4-Amino-7-(morpholinomethyl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1: 4-Aminopyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde

To a solution of pyrrolo[2,1-f][1,2,4]triazin-d-amine (1.0 g, 7.45 mmol)in DMF (15 mL) at 0° C. was added POCl₃ (3.47 mL, 37.3 mmol). Thereaction mixture was then stirred at 60° C. overnight, cooled to rt,quenched with saturated NaHCO₃ solution, and extracted with EtOAc (30mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, concentrated, and purified via column chromatography (0% to 15%MeOH in CH₂Cl₂) to give the product (200 mg, 16%). LCMS calcd forC₇H₇N₄O (M+H)⁺: m/z=163.1. Found: 163.1.

Step 2: 4-Amino-5-bromopyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde

To a solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde(200 mg, 1.23 mmol) in THF (6.0 ml) at rt was added1,3-dibromo-5,5-dimethylhydantoin (212 mg, 0.74 mmol) portionwise. Thereaction mixture was then stirred at rt for 1 h, and diluted with water(30 mL)/EtOAc (30 mL). The organic layer was separated, washed withbrine, dried over Na₂SO₄, and concentrated to give the product (127 mg,43%), which was used directly in the next step. LCMS calcd for C₇H₆BrN₄O(M+H)⁺: m/z=241.0. Found: 241.0.

Step 3:N-(4-(4-Amino-7-formylpyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

A mixture of 4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde(126 mg, 0.52 mmol),1-isopropyl-2,4-dioxo-3-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide(248 mg, 0.52 mmol) (from example 61, step 5),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2) (41 mg, 0.052 mmol), and Na₂CO₃ (111 mg, 1.04 mmol) in1,4-dioxane (4.0 mL)/water (1.0 mL) was purged with N₂, and stirred at70° C. for 2 h. The reaction mixture was then cooled to rt, and dilutedwith water (30 mL)/EtOAc (30 mL). The organic layer was separated,washed with brine, dried over Na₂SO₄, concentrated, and purified viacolumn chromatography (0% to 15% MeOH in CH₂Cl₂) to give the product(266 mg, 100%). LCMS calcd for C₂₇H₂₄N₇O₄ (M+H)⁺: m/z=510.2. Found:510.2.

Step 4:N-(4-(4-Amino-7-(morpholinomethyl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture ofN-(4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(20 mg, 0.039 mmol), morpholine (0.017 mL, 0.20 mmol), and acetic acid(0.011 mL, 0.20 mmol) in ClCH₂CH₂Cl (1.5 mL) at rt was added sodiumtriacetoxyborohydride (42 mg, 0.20 mmol). The reaction mixture was thenstirred at 50° C. for 15 min, cooled to rt, concentrated, diluted withMeOH, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) togive the product as a white solid (TFA salt). LCMS calcd for C₃₁H₃₃N₈O₄(M+H)⁺: m/z=581.3. Found: 581.3.

Example 96.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

Step 1: N-Phenylhydrazinecarbothioamide

To a stirred solution of hydrazine hydrate (1.7 g, 34 mmol) in isopropylalcohol (300 mL) at rt was added isothiocyanatobenzene (3.4 mL). Thereaction mixture was stirred at rt for 30 min, and the resulting solidwas collected by filtration, washed with isopropanol, and dried to givethe product (4.8 g). LCMS calcd for C₇H₁₀N₃S (M+H)⁺: m/z=168.1. Found:168.1.

Step 2: Ethyl5-oxo-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate

A mixture of propanedioic acid, oxo-, diethyl ester (5.0 mL, 33 mmol)and N-phenylhydrazinecarbothioamide (5.5 g, 33 mmol) in EtOH (100 mL)was refluxed for 3 days. The reaction mixture was cooled to rt, and theresulting solid was collected by filtration, washed with cold EtOH, anddried to give the product (6 g, 66%). LCMS calcd for C₁₂H₁₂N303S (M+H)⁺:m/z=278.1. Found: 278.2.

Step 3: Ethyl3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate

A mixture of ethyl5-oxo-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate(6.0 g, 22 mmol), H₂O₂ (30 wt % in water, 6.4 mL) and acetic acid (20mL) in DMF (60 mL) was stirred at rt overnight. The reaction mixture wasthen diluted with EtOAc, washed with water, brine, dried, andconcentrated. The resulting solid was triturated with ether to give theproduct. LCMS calcd for C₁₂H₁₂N₃O₄ (M+H)⁺: m/z=262.1. Found: 262.2.

Step 4: Ethyl2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate

Isopropyl iodide (0.46 mL, 4.6 mmol) was added to a mixture of ethyl3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (0.6g, 2 mmol) and K₂CO₃ (0.95 g, 6.9 mmol) in DMF (7 mL). The reactionmixture was stirred at 65° C. for 2 h, cooled to rt, diluted with EtOAc,and washed with saturated NaHCO₃ solution, water, and brine. The organiclayer was separated, dried over Na₂SO₄, and concentrated to provide theproduct. LCMS calcd for C₁₅H₁₈N₃O₄ (M+H)⁺: m/z=304.1. Found: 304.1.

Step 5:2-Isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicAcid

A mixture of ethyl2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate(1.0 g, 3.4 mmol) and water (1.0 mL) in 4 M HCl in 1,4-dioxane (10 mL)was stirred at 70° C. overnight. The reaction mixture was cooled to rt,diluted with water, and extracted with EtOAc. The combined organiclayers were dried over MgSO₄ and concentrated to provide the desiredproduct. LCMS calcd for C₁₃H₁₄N₃O₄ (M+H)⁺: m/z=276.1. Found: 276.0.

Step 6: tert-Butyl4-[4-amino-5-(4-{[(2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

To a mixture of tert-butyl4-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate(150 mg, 0.37 mmol) (from example 107, step 4) and2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (101 mg, 0.37 mmol) in DMF (1.7 mL) was added Et₃N (77 μL, 0.55mmol) followed by HATU (0.168 g, 0.44 mmol). The reaction mixture wasstirred at rt for 1 h, quenched with water, and the resulting solid wascollected by filtration, and dried to give the product (0.2 g, 80%).LCMS calcd for C₃₅H₄₀N₉O₅ (M+H)⁺: m/z=666.3. Found: 666.2.

Step 7:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

4 M HCl in 1,4-dioxane (0.71 mL, 2.8 mmol) was added to a mixture oftert-butyl4-[4-amino-5-(4-{[(2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate(0.20 g, 0.30 mmol) in CH₂Cl₂ (0.47 mL). The mixture was stirred at rtfor 1 h, and concentrated to give the product (0.17 g, 100%). LCMS calcdfor C₃₀H₃₂N₉O₃ (M+H)⁺: m/z=566.3. Found: 566.2.

Step 8:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

Isobutyryl chloride (0.0044 g, 0.041 mmol) was added to a solution ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-2-isopropyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide(20 mg, 0.03 mmol) and Et₃N (24 μL, 0.17 mmol) in CH₂Cl₂ (1.1 mL). Thereaction mixture was stirred at rt for 4 h, and directly purified via pH2 preparative LC/MS (MeCN/water with TFA) to give the product as TFAsalt. LCMS calcd for C₃₄H₃₈N₉O₄ (M+H)⁺: m/z=636.3. Found: 636.3.

Example 97.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide

Step 1:(E/Z)-3-((Dimethylamino)methylene)-6-methyl-2H-pyran-2,4(3H)-dione

To a solution of 6-methyl-2H-pyran-2,4(3H)-dione (13 g, 103 mmol) intoluene (30 mL) was added N,N-dimethylformamide dimethyl acetal (15 ml,113 mmol). The resulting solution was stirred at rt for 36 h, andconcentrated to give a red solid, which was used directly in the nextstep. LCMS calcd for C₉H₁₂NO₃ (M+H)⁺: m/z=182.1. Found: 182.1.

Step 2: 1-Isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic Acid

To a 250 mL round-bottomed flask was added(E/Z)-3-((dimethylamino)methylene)-6-methyl-2H-pyran-2,4(3H)-dione (2.0g, 11.0 mmol), propan-2-amine (1.41 mL, 16.6 mmol) and sodiumtert-butoxide (1.57 g, 16.3 mmol) in EtOH (80 mL). The round bottom wasequipped with an air condenser and the resulting mixture was stirred at90° C. for 18 h, cooled to rt, concentrated, and treated with water andCH₂Cl₂. The solution was acidified with 4 N HCl solution and uponseparation the aqueous layer was extracted with CH₂Cl₂. The combinedorganic layers were washed with water, brine, dried over Na₂SO₄, andconcentrated to give the crude product, which was used directly in thenext step. LCMS calcd for C₁₀H₁₄NO₃ (M+H)⁺: m/z=196.1. Found: 196.1.

Step 3:5-Bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic Acid

To a solution of1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (219mg, 1.12 mmol) in DCE (5 mL) was added NBS (295 mg, 1.66 mmol) and theresulting solution was stirred at rt overnight, diluted with water, andupon separation the aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with water, brine, dried overNa₂SO₄, and concentrated to give the crude product, which was useddirectly in the next step. LCMS calcd for C₁₀H₁₃BrNO₃ (M+H)⁺: m/z=274.0.Found: 274.0.

Step 4:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide

To a solution of5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid(154 mg, 0.56 mmol) and HATU (256 mg, 0.67 mmol) in DCE (5 mL) was addedDIPEA (0.24 mL, 1.41 mmol) and1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(213 mg, 0.56 mmol) (from example 83, step 2). The resulting solutionwas stirred at rt overnight, and purified via column chromatography (0%to 100% EtOAc in hexanes) to give the product. LCMS calcd forC₃₁H₃₇BrN₇O₃ (M+H)⁺: m/z=634.2. Found: 634.2.

Step 5:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide(62 mg, 0.098 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (61.5 mg,0.489 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Xphos Pd G2) (11.53 mg, 0.015 mmol), and potassiumphosphate tribasic (0.024 ml, 0.29 mmol) in 1,4-dioxane (2.0 ml) andwater (0.40 ml) was degassed and purged with N₂ several times prior toheating in a sealed vial at 90° C. overnight. After cooling to rt, themixture was diluted with MeOH, filtered, and purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₅H₄₂N₉O₃ (M+H)⁺: m/z=636.3. Found: 636.4. ¹H NMR (600MHz, DMSO) δ 12.87 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.82 (d, J=8.7Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 6.73 (s, 1H),6.21 (d, J=1.8 Hz, 1H), 4.85-4.76 (m, 1H), 4.55 (d, J=12.9 Hz, 1H), 4.08(d, J=13.1 Hz, 1H), 3.61 (s, 3H), 3.42 (dd, J=11.9, 3.7 Hz, 1H),3.28-3.16 (m, 1H), 2.98-2.86 (m, 1H), 2.77-2.64 (m, 1H), 2.33 (s, 3H),2.13-1.96 (m, 2H), 1.71-1.58 (m, 1H), 1.58-1.47 (m, 7H), 1.08-0.97 (m,6H).

Example 98.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5′-fluoro-1-isopropyl-2-methyl-4-oxo-1,4-dihydro-[3,3′-bipyridine]-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 97, using (5-fluoropyridin-3-yl)boronic acid instead of(1-methyl-1 n-pyrazol-5-yl)boronic acid. This compound was purified viapH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFAsalt. LCMS calcd for C₃₆H₄₀FN₈O₃ (M+H)⁺: m/z=651.3. Found: 651.3. ¹H NMR(500 MHz, DMSO) δ 12.86 (s, 1H), 8.74 (s, 1H), 8.61 (d, J=2.8 Hz, 1H),8.34 (m, 1H), 8.08 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.71 (m, 1H), 7.47(d, J=8.6 Hz, 2H), 6.75 (s, 1H), 4.83 (m, 1H), 4.56 (m, 1H), 4.09 (m,1H), 3.42 (m, 1H), 3.21 (m, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.34 (s,3H), 2.02 (m, 2H), 1.64 (m, 1H), 1.53 (m, 7H), 1.02 (m, 6H).

Example 99.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-(3-cyanophenyl)-1-isopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 97, using (3-cyanophenyl)boronic acid instead of(1-methyl-1 n-pyrazol-5-yl)boronic acid. This compound was purified viapH 2 preparative LC/MS (MeCN/water with TFA) to give the product as TFAsalt. LCMS calculated for C₃₈H₄₁N₈O₃ (M+H)⁺: m/z=657.3; Found: 657.3. ¹HNMR (500 MHz, DMSO) δ 12.91 (s, 1H), 8.73 (s, 1H), 8.08 (s, 1H), 7.87(m, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.74 (m, 1H), 7.69 (m, 1H), 7.61 (m,1H), 7.46 (d, J=8.6 Hz, 2H), 6.75 (s, 1H), 4.81 (m, 1H), 4.55 (m, 1H),4.08 (m, 1H), 3.42 (m, 1H), 3.21 (m, 1H), 2.90 (m, 1H), 2.77-2.61 (m,1H), 2.30 (s, 3H), 2.13-1.89 (m, 2H), 1.65 (m, 1H), 1.52 (m, 7H), 1.02(m, 6H).

Example 100.N-(4-(4-Amino-6-bromo-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-4-methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: 4-Methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic Acid

A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.40g, 8.28 mmol) (from Enamine Ltd.), phenylboronic acid (4.04 g, 33.1mmol), activated 4 Å molecular sieves (2.59 g) and copper (II) acetate(4.51 g, 24.8 mmol) in CH₂Cl₂ (50 mL) was treated with pyridine (2.68mL) and stirred at rt for 3 days. The reaction mixture was then dilutedwith MeOH, filtered, concentrated, and purified via columnchromatography (0% to 100% MeOH in EtOAc) to afford the product as alight greenish powder (244 mg, 12%). LCMS calcd for C₁₃H₁₂NO₄ (M+H)⁺:m/z=246.1. Found: 246.1.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-4-methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a mixture of 4-methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (35 mg, 0.14 mmol) and1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(59.4 mg, 0.16 mmol) (from example 83, step 2) in DMF (571 μL) was addedEt₃N (60 μL), followed by HATU (109 mg, 0.29 mmol). The resultingmixture was stirred at rt for 30 min, filtered, and the crude materialwas purified via column chromatography (0% to 30% MeOH in EtOAc) to givethe desired product as a light yellow powder (70 mg, 81%). LCMS calcdfor C₃₄H₃₆N₇O₄ (M+H)⁺: m/z=606.3. Found: 606.3.

Step 3:N-(4-(4-Amino-6-bromo-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-4-methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a solution ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-4-methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(61 mg, 0.10 mmol) in DMF (403 μL) was added NBS (19 mg, 0.11 mmol). Theresulting mixture was stirred at rt for 5 min, diluted with EtOAc/THF,filtered, washed with saturated NaHCO₃ solution, water, brine, driedover Na₂SO₄, and concentrated. The crude material was purified via pH 10preparative LC/MS (MeCN/water with NH₄OH) to give the product as anoff-white powder. LCMS calcd for C₃₄H₃₅BrN₇O₄ (M+H)⁺: m/z=684.2. Found:684.2.

Example 101.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-(5-fluoropyridin-3-yl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Step 1:5-Bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxylic Acid

Ethyl5-bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxylate (1.0g, 2.82 mmol) (from Affinity Research Chemicals) was dissolved in THF(10 mL) and ethanol (6.7 mL). The mixture was then treated with 1 M NaOHin water (11 mL), and the reaction mixture was stirred at 25° C. for 20min. The resulting mixture was neutralized with 12 M HCl solution to pH6˜7 and the organic solvents were removed under vacuum. The resultingmixture was extracted with EtOAc. The combined organic layers weredried, and concentrated to give the product as a light brown powder (975mg). LCMS calcd for C₁₂H₉BrFN₂O₃ (M+H)⁺: m/z=327.0. Found: 327.0.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

To a mixture of5-bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxylic acid(38 mg, 0.069 mmol) and1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(25 mg, 0.066 mmol) (from example 83, step 2) in DMF (264 μL) was addedEt₃N (28 μL), followed by HATU (50 mg, 0.13 mmol). The resulting mixturewas stirred at rt for 20 min, and the crude material was purified via pH2 preparative LC/MS (MeCN/water with TFA) to give the product as anoff-white powder (TFA salt). LCMS calcd for C₃₃H₃₃BrFN₈O₃ (M+H)⁺:m/z=687.2. Found: 687.2. ¹H NMR (600 MHz, DMSO) δ 11.64 (s, 1H), 8.84(d, J=2.6 Hz, 1H), 8.62 (d, J=12.6 Hz, 2H), 8.12 (dt, J=9.2, 2.3 Hz,1H), 8.06 (s, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 6.73(s, 1H), 4.55 (d, J=12.6 Hz, 1H), 4.07 (d, J=14.0 Hz, 1H), 3.42 (tt,J=12.0, 3.5 Hz, 1H), 3.21 (t, J=12.9 Hz, 1H), 2.91 (dt, J=13.5, 6.7 Hz,1H), 2.75-2.66 (m, 2H), 2.25 (s, 3H), 2.04 (dd, J=30.5, 13.5 Hz, 2H),1.72 (m, 1H), 1.60 (m, 1H), 1.52 (d, J=12.1 Hz, 1H), 1.05-0.99 (m, 6H).

Example 102.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-(cyanomethyl)-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

To a stirred mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide(8.0 mg, 0.012 mmol) (from example 101, step 2), isoxazol-4-ylboronicacid (2.0 mg, 0.02 mmol), 1,4-dioxane (200 μL),A-ethyl-A-isopropylpropan-2-amine (4.5 mL) and water (40 μL) was addedPd(tBu₃)₂ (3.0 mg, 5.8 μmol). The reaction mixture was then heated at110° C. for 60 min, cooled to rt, diluted with DMF, and purified via pH10 preparative LC/MS (MeCN/water with NH₄OH) to give the product as anoff-white powder. LCMS calcd for C₃₅H₃₅FN₉O₃ (M+H)⁺: m/z=648.3. Found:648.3.

Example 103.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5′-fluoro-6-methyl-2-oxo-5-(thiazol-4-yl)-2n-[1,3′-bipyridine]-3-carboxamide

To a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide(8.0 mg, 0.012 mmol) and Pd(Ph₃P)₄ (2.7 mg, 2.3 μmol) in toluene (0.30mL) was added 4-(tributylstannyl)thiazole (8.7 mg, 0.023 mmol). Thereaction mixture was sealed in a microwave vial, vacuumed and backfilledwith N₂ several times, and heated at 120° C. for 20 h. The reactionmixture was cooled to rt, and the crude material was purified via pH 10preparative LC/MS (MeCN/water with NH₄OH) to give the product as anoff-white powder. LCMS calcd for C₃₆H₃₅FN₉O₃S (M+H)⁺: m/z=692.3. Found:692.3.

Example 104.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-oxo-1-phenyl-1,6-dihydro-[2,2′-bipyridine]-5-carboxamide

Step 1: 6-Oxo-1-phenyl-1,6-dihydro-[2,2′-bipyridine]-5-carbonitrile

A mixture of 2-cyano-A-phenylacetamide (1.60 g, 10.0 mmol),3-(dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one (1.94 g, 11.0 mmol)and 1,4-diazabicyclo[2.2.2]octane (0.98 mL, 10.0 mmol) in EtOH (20 mL)was heated at 90° C. overnight. After cooling to rt, the reactionmixture was concentrated, and partitioned between CH₂Cl₂ (60 mL) and 2 MHCl solution (20 mL). The organic layer was separated, washed withwater, dried over MgSO₄, concentrated, and purified via columnchromatography (20% to 100% EtOAc in hexanes) to afford the product(1.25 g, 46%). LCMS calcd for C₁₇H₁₂N₃O (M+H)⁺: m/z=274.1. Found: 274.2.

Step 2: 6-Oxo-1-phenyl-1,6-dihydro-[2,2′-bipyridine]-5-carboxylic Acid

6-Oxo-1-phenyl-1,6-dihydro-[2,2′-bipyridine]-5-carbonitrile (0.20 g,0.73 mmol) in concentrated sulfuric acid (1.5 mL) and water (1.5 mL) washeated at 120° C. for 3 h. After cooling to rt, the reaction mixture wascarefully neutralized at 0° C. with 10% NaOH solution to pH˜7. Theresulting mixture was extracted with 9:1 CH₂Cl₂/MeOH (5 mL×3), and thecombined organic layers were dried over Na₂SO₄, and concentrated to givethe crude product (0.19 g, 89%), which was used directly in the nextstep. LCMS calcd for C₁₇H₁₃N₂O₃ (M+H)⁺: m/z=293.1. Found: 293.1.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-oxo-1-phenyl-1,6-dihydro-[2,2′-bipyridine]-5-carboxamide

To a mixture of6-oxo-1-phenyl-1,6-dihydro-[2,2′-bipyridine]-5-carboxylic acid (0.015 g,0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (3 mL) was added1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(0.019 g, 0.0500 mmol) (from example 83, step 2) and Et₃N (0.021 ml,0.15 mmol). The mixture was stirred at rt until completion, diluted withMeOH, adjusted with TFA to pH 2, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₈H₃₇N₈O₃ (M+H)⁺: m/z=653.3. Found: 653.3.

Example 105.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6′-methyl-6-oxo-1-phenyl-1,6-dihydro-[2,3′-bipyridine]-5-carboxamide

Step 1: 3-(Dimethylamino)-1-(6-methylpyridin-3-yl)prop-2-en-1-one

A mixture of 1-(6-methylpyridin-3-yl)ethan-1-one (2.50 g, 18.5 mmol) and1,1-dimethoxy-N,N-dimethylmethanamine (4.41 g, 37.0 mmol) was heated at100° C. for 8 h, cooled to rt, and concentrated. The resulting residuewas triturated with ether. The solid was then collected by filtrationand washed with ether to afford the crude product (2.75 g, 78%). LCMScalcd for C₁₁H₁₅N₂O (M+H)⁺: m/z=191.1. Found: 191.1.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6′-methyl-6-oxo-1-phenyl-1,6-dihydro-[2,3-bipyridine]-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothose for example 104, from step 1 to step 3, using3-(dimethylamino)-1-(6-methylpyridin-3-yl)prop-2-en-1-one instead of3-(dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one. This compound waspurified via pH 2 preparative LC/MS (MeCN/water with TFA) to give theproduct as TFA salt. LCMS calcd for C₃₉H₃₉N₈O₃ (M+H)⁺: m/z=667.3. Found:667.3.

Example 106.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-methyl-6-oxo-1-phenyl-1,6-dihydro-[2,3′-bipyridine]-5-carboxamide

Step 1: 3-(Dimethylamino)-2-methyl-1-(pyridin-3-yl)prop-2-en-1-one

This compound was prepared following a synthetic sequence analogous tothose for example 105, step 1, using 1-(pyridin-3-yl)propan-1-oneinstead of 1-(6-methylpyridin-3-yl)ethan-1-one. LCMS calcd for C₁₁H₁₅N₂O(M+H)⁺: m/z=191.1. Found: 191.1.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-methyl-6-oxo-1-phenyl-1,6-dihydro-[2,3-bipyridine]-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothose for example 104, from step 1 to step 3, using3-(dimethylamino)-2-methyl-1-(pyridin-3-yl)prop-2-en-1-one instead of3-(dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one. This compound waspurified via pH 2 preparative LC/MS (MeCN/water with TFA) to give theproduct as TFA salt. LCMS calcd for C₃₉H₃₉N₈O₃ (M+H)⁺: m/z=667.3. Found:667.3.

Example 107.N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile

To a mixture of 2-cyano-A-phenylacetamide (5.0 g, 31.2 mmol) and4-methoxy-3-butene-2-one (6.2 g, 62 mmol) in 2-(2-methoxyethoxy)ethanol(75 mL) was added DABCO (3.50 g, 31.2 mmol). The resulting mixture wasstirred at 120° C. overnight, cooled to rt, concentrated, and theresulting material was partitioned between CH₂Cl₂ (300 mL) and 2 M HClsolution (100 mL). The organic layer was separated, washed with water,dried over MgSO₄, concentrated, and added EtOAc. The mixture was stirredfor 30 min, and the resulting solid was collected by filtration anddried to give the product (3.17 g). The filtrate was concentrated andpurified via column chromatography (20% to 90% EtOAc in hexanes) to givean additional 1.58 g of the product as a brown solid (72% combined).LCMS calcd for C₁₃H₁₁N₂O (M+H)⁺: m/z=211.1. Found: 211.1.

Step 2: 6-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic Acid

A mixture of 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile(3.17 g, 15.1 mmol) and KOH (3.47 g, 61.8 mmol) in EtOH (34 mL)/water(8.0 mL) was stirred at 90° C. for 46 h. EtOH was evaporated and theresulting mixture was diluted with water and washed with CH₂Cl₂. Theaqueous layer was then acidified with 2 N HCl solution, and extractedwith CH₂C₂. The combined organic layers were dried over MgSO₄, andconcentrated to give the product (2.2 g, 64%). LCMS calcd for C₁₃H₁₂NO₃(M+H)⁺: m/z=230.1. Found: 230.1.

Step 3: 5-Bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylicAcid

To a solution of6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (2.20 g,9.6 mmol) in DMF (30 mL) was added NBS (1.70 g, 9.55 mmol). The reactionmixture was stirred at rt for 4 h, added more NBS (300 mg), and stirredovernight. Water (100 mL) was then added to the reaction mixture at 0°C., and stirring continued for 20 min. The resulting solid was collectedby filtration, washed with water, and dried to give the product as a tansolid (2.4 g, 81%). LCMS calcd for C₁₃H₁₁BrNO₃ (M+H)⁺: m/z=308.0. Found:308.0.

Step 4: tert-Butyl4-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

A mixture of tert-butyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(400 mg, 1 mmol) (from example 32, step 3),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (265 mg, 1.21mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (39.7 mg, 0.051 mmol), and potassium phosphate (643 mg, 3.03 mmol)in 1,4-dioxane (9 mL)/water (1.6 mL) was degassed with N₂ and thenstirred at 90° C. overnight. The reaction mixture was cooled to rt,diluted with EtOAc, filtered through Celite, concentrated, and purifiedvia column chromatography (10% to 100% EtOAc in hexanes, then 10% MeOHin EtOAc) to give the product (200 mg, 50%). LCMS calcd for C₂₂H₂₉N₆O₂(M+H)⁺: m/z=409.2. Found: 409.2.

Step 5: tert-Butyl4-[4-amino-5-(4-{[(5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate

To a mixture of tert-butyl4-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate(100 mg, 0.25 mmol) and5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid(75 mg, 0.25 mmol) in DMF (1.5 mL) was added Et₃N (51 uL, 0.37 mmol),followed by HATU (112 mg, 0.29 mmol). The resulting mixture was stirredat rt overnight, added water, and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, concentrated, and purified viacolumn chromatography (10% to 80% EtOAc in hexanes, then 10% MeOH inEtOAc) to give the product (95 mg, 56%). LCMS calcd for C₃₅H₃₇BrN₇O₄(M+H)⁺: m/z=698.2. Found: 698.3.

Step 6: tert-Butyl4-{4-amino-5-[4-({[6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridin-3-yl]carbonyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate

A mixture of tert-butyl4-[4-amino-5-(4-{[(5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate(95 mg, 0.14 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(34.0 mg, 0.16 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (5.3 mg, 0.0068 mmol), and potassium phosphate (87 mg, 0.41 mmol)in 1,4-dioxane (1.3 mL)/water (0.30 mL) was degassed with N₂ and stirredat 90° C. for 3 h. The resulting mixture was cooled to rt, diluted withCH₂Cl₂/water, and filtered through Celite. The organic layer wasseparated, and concentrated to give the crude product (88 mg), which wasused directly in the next step. LCMS calcd for C₃₉H₄₂N₉O₄ (M+H)⁺:m/z=700.3. Found: 700.4.

Step 7:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a solution of tert-butyl4-{4-amino-5-[4-({[6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridin-3-yl]carbonyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate(87 mg, 0.12 mmol) in CH₂Cl₂ (2 mL) was added TFA (1 mL). The resultingmixture was stirred at rt for 1 h, concentrated, and dried to give theproduct (90 mg) as TFA salt. LCMS calculated for C₃₄H₃₄N₉O₂ (M+H)⁺:m/z=600.3; Found: 600.2.

Step 8:N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a mixture ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(60 mg, 0.084 mmol) and Et₃N (59 uL, 0.42 mmol) in CH₂Cl₂ (1 mL) wasadded isobutyryl chloride (12 uL, 0.11 mmol). The resulting mixture wasstirred at rt for 90 min, and directly purified via pH 2 preparativeLC/MS (MeCN/water with TFA) to give the product as TFA salt. LCMScalculated for C₃₈H₄₀N₉O₃ (M+H)⁺: m/z=670.3; Found: 670.2. ¹H NMR (600MHz, DMSO) δ 12.05 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H),7.81 (d, J=8.7 Hz, 2H), 7.64-7.59 (m, 3H), 7.57-7.52 (m, 1H), 7.45-7.41(m, 4H), 6.69 (s, 1H), 4.53 (d, J=12.3 Hz, 1H), 4.05 (d, J=12.9 Hz, 1H),3.89 (s, 3H), 3.43-3.34 (m, 1H), 3.24-3.15 (m, 1H), 2.89 (hept, 6.7 Hz,1H), 2.68 (t, J=12.0 Hz, 1H), 2.09 (s, 3H), 2.02 (dd, J=32.4, 13.2 Hz,2H), 1.56 (dd, J=72.6, 9.9 Hz, 2H), 1.03-0.97 (m, 6H).

Example 108.N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxamide

Step 1: Ethyl5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate

A mixture of5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid(1.0 g, 3.24 mmol) (example 107, step 3) and sulfuric acid (180 uL, 3.4mmol) in EtOH (60 mL) was refluxed for 3 days, cooled to rt, andconcentrated. The resulting residue was dissolved in CH₂Cl₂, washed withsaturated NaHCO₃ solution, dried over MgSO₄, and concentrated to givethe product as a brown solid (1 g). LCMS calcd for C₁₅H₁₅BrNO₃ (M+H)⁺:m/z=336.0; Found: 336.1.

Step 2: Ethyl6-methyl-2-oxo-1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carboxylate

A mixture of ethyl5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (520mg, 1.5 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (786 mg,3.09 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (57 mg, 0.077 mmol), and potassium acetate (455 mg, 4.64 mmol) in1,4-dioxane (13 mL) was degassed with N2 for 5 min, and then stirred at90° C. for 17 h, cooled to rt, and filtered through a plug of Celite(washed with EtOAc). The filtrate was washed with brine, dried overNa₂SO₄, and concentrated. The crude material was purified via columnchromatography (15% to 65% EtOAc in hexanes) to give the product (168mg, 28%). LCMS calcd for C₂₁H₂₇BNO₅ (M+H)⁺: m/z=384.2; Found: 384.2.

Step 3: Ethyl6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxylate

In a sealed microwave vial, a mixture of ethyl6-methyl-2-oxo-1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-3-carboxylate(168 mg, 0.44 mmol), 2-bromopyrimidine (83.6 mg, 0.53 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (17 mg, 0.022 mmol) and potassium phosphate (279 mg, 1.32 mmol) in1,4-dioxane (5 mL)/water (1 mL) was stirred at 90° C. for 2.5 h. Thereaction mixture was then cooled to rt, diluted with CH₂C₁₋₂/water, andfiltered through Celite. The organic layer was separated andconcentrated to give the crude product (127 mg, 86%), which was useddirectly in the next step. LCMS calcd for C₁₉H₁₈N₃O₃ (M+H)⁺: m/z=336.1;Found: 336.1.

Step 4:6-Methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxylicAcid

To a solution of ethyl6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxylate(127 mg, 0.38 mmol) in MeOH (2 mL)/water (0.4 mL) was added Lithiumhydroxide, monohydrate (79 mg, 1.89 mmol). The resulting mixture wasstirred at 40° C. for 3 h, and MeOH was evaporated. This mixture wasacidified with IN HCl solution, and the resulting solid was collected byfiltration, washed with water, and dried to give the product (80 mg,70%). LCMS calcd for C₁₇H₁₄N₃O₃ (M+H)⁺: m/z=308.1; Found: 308.0.

Step 5:6-Methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(57 mg, 0.26 mmol) and6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxylicacid (80 mg, 0.3 mmol) in DMF (1.6 mL) was added Et₃N (54 uL, 0.390mmol), followed by HATU (119 mg, 0.31 mmol). The resulting mixture wasstirred at rt overnight, added water, and the resulting solid wascollected by filtration, washed with water, and dried to give theproduct as a white solid (103 mg, 78%). LCMS calcd for C₂₉H₃₀BN₄O₄(M+H)⁺: m/z=509.2; Found: 509.2.

Step 6:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-1-phenyl-5-(pyrimidin-2-yl)-1,2-dihydropyridine-3-carboxamide

A mixture of tert-butyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(21 mg, 0.053 mmol) (from example 32, step 3),6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(32 mg, 0.064 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.0 mg, 0.0027 mmol), and potassium phosphate (34 mg, 0.16 mmol)in 1,4-dioxane (0.65 mL)/water (0.1 mL) was degassed with N₂, and thenstirred at 90° C. for 2 h. The reaction mixture was cooled to rt,diluted with CH₂C₁₋₂/water, and filtered through Celite. The organiclayer was separated, concentrated, and added CH₂Cl₂ (0.4 mL) and 4 M HClin 1,4-dioxane (120 uL, 0.48 mmol). The resulting mixture was stirred atrt overnight, and concentrated to give the crude product (30 mg), whichwas used directly in the next step. LCMS calcd for C₃₄H₃₂N₉O₂ (M+H)⁺:m/z=598.3; Found: 598.2.

Step 7:N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothose for example 107, step 8, usingN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-1-phenyl-5-(pyrimidin-2-yl)-1,2-dihydropyridine-3-carboxamideinstead ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide.This compound was purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as TFA salt. LCMS calculated for C₃₈H₃₈N₉O₃(M+H)⁺: m/z=668.3; Found: 668.2. ¹H NMR (600 MHz, DMSO) δ 11.89 (s, 1H),9.16 (s, 1H), 8.96 (d, J=4.9 Hz, 2H), 8.08 (s, 1H), 7.83 (d, J=8.7 Hz,2H), 7.63 (t, J=7.7 Hz, 2H), 7.59-7.53 (m, 1H), 7.51-7.44 (m, 5H), 6.74(s, 1H), 4.53 (d, J=12.3 Hz, 1H), 4.06 (d, J=12.7 Hz, 1H), 3.48-3.33 (m,1H), 3.19 (t, J=12.4 Hz, 1H), 2.89 (hept, J=6.7 Hz, 1H), 2.68 (t, J=11.9Hz, 1H), 2.40 (s, 3H), 2.01 (dd, J=30.0, 12.2 Hz, 2H), 1.56 (dd, J=74.3,9.4 Hz, 2H), 1.00 (d, J=3.9 Hz, 6H).

Example 109.N-{4-[4-Amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxamide

To a mixture of5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(from example 20, step 3) (31 mg, 0.10 mmol),6-methyl-2-oxo-1-phenyl-5-pyrimidin-2-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide(61 mg, 0.12 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (3.9 mg, 0.0050 mmol), and potassium phosphate (64 mg, 0.30 mmol)in 1,4-dioxane (1.2 mL)/water (0.2 mL) was degassed with N₂ and thenstirred at 90° C. for 3 h. The reaction mixture was cooled to rt,diluted with MeOH, filtered, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₅H₃₄N₉O₂ (M+H)⁺: m/z=612.3; Found: 612.2. ¹H NMR (600 MHz, DMSO) δ11.87 (s, 1H), 9.17 (s, 1H), 8.96 (d, J=4.9 Hz, 2H), 7.97 (s, 1H), 7.83(d, J=8.7 Hz, 2H), 7.63 (t, J=7.7 Hz, 2H), 7.59-7.53 (m, 1H), 7.51-7.47(m, 3H), 7.44 (d, J=8.6 Hz, 2H), 6.62 (s, 1H), 3.61-3.43 (m, 2H),3.42-3.32 (m, 1H), 3.16 (q, J=10.4 Hz, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41(s, 3H), 2.26 (d, J=14.3 Hz, 2H), 1.93-1.85 (m, 2H).

Example 110.N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-5-morpholin-4-yl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:N-[4-(4-Amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-6-methyl-5-morpholin-4-yl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A mixture of tert-butyl4-[4-amino-5-(4-{[(5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate(52 mg, 0.074 mmol) (from example 107, step 5) and morpholine (0.10 mL,1.1 mmol) in DMF (1 mL) was heated at 180° C. under microwave conditionsfor 60 min, cooled to rt, purified via pH 2 preparative LC/MS(MeCN/water with TFA), and concentrated (de-Boc occurred during thisprocess) to give the product as TFA salt. LCMS calculated for C₃₄H₃₇N₈O₃(M+H)⁺: m/z=605.3; Found: 605.4.

Step 2:N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-methyl-5-morpholin-4-yl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothose for example 107, step 8, usingN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-6-methyl-5-morpholin-4-yl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideinstead ofN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide.This compound was purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as TFA salt. LCMS calculated for C₃₈H₄₃N₈O₄(M+H)⁺: m/z=675.3; Found: 675.3.

Example 111.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: Ethyl5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate

A mixture of ethyl5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (300mg, 0.89 mmol) (from example 108, step 1), Pd₂(dba)₃ (32.7 mg, 0.036mmol), Xantphos (41 mg, 0.071 mmol), Zinc cyanide (105 mg, 0.89 mmol)and TMEDA (0.040 ml, 0.27 mmol) in DMF (2.5 ml) was degassed with N₂,and then stirred at 160° C. under microwave conditions for 10 min. Aftercooling to rt, the reaction mixture was filtered through Celite (washedwith CH₂Cl₂), and concentrated to give the crude product (0.32 g), whichwas used directly in the next step. LCMS calcd for C₁₆H₁₅N₂O₃ (M+H)⁺:m/z=283.1; Found: 283.1.

Step 2: 5-Cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylicAcid

A mixture of ethyl5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (250mg, 0.89 mmol) and lithium hydroxide monohydrate (186 mg, 4.43 mmol) inMeOH (7.0 ml)/water (0.70 ml) was stirred at rt for 5 h, and MeOH wasevaporated. Water was added and the resulting mixture was acidified withIN HCl solution, stirred for another 10 min, filtered, and extractedwith CH₂Cl₂. The combined organic layers were dried over MgSO₄, andconcentrated to give the product (147 mg, 65%). LCMS calculated forC₁₄H₁₁N₂O₃ (M+H)⁺: m/z=255.1; Found: 255.0.

Step 3: tert-butyl4-(4-amino-5-(4-(5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(200 mg, 0.49 mmol) (from example 107, step 4),5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid(124 mg, 0.49 mmol), and Et₃N (0.102 mL, 0.73 mmol) in DMF (4 mL) wasadded HATU (223 mg, 0.59 mmol). The resulting mixture was stirred at rtovernight, added water, and the resulting solid was collected byfiltration, washed with water, and dried to give a light yellow solid(307 mg). LCMS calcd for C₃₆H₃₇N₈O₄ (M+H)⁺: m/z=645.3; Found: 645.4.

Step 4:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a solution of tert-butyl4-(4-amino-5-(4-(5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(300 mg, 0.47 mmol) in CH₂Cl₂ (4.5 ml) was added 4 M HCl in 1,4-dioxane(0.93 mL, 3.72 mmol). The resulting mixture was stirred at rt for 4 h,added EtOAc, and the resulting solid was collected by filtration, washedwith EtOAc, and dried to give the product as a HCl salt (286 mg). LCMScalculated for C₃₁H₂₉N₈O₂ (M+H)⁺: m/z=545.2; Found: 545.2.

Step 5:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothose for example 107, step 8, usingN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-cyano-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideinstead ofN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide.This compound was purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as TFA salt. LCMS calculated for C₃₅H₃₅N₈O₃(M+H)⁺: m/z=615.3; Found: 615.3.

Example 111a.N³-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarboxamide

This compound was generated as a by-product from the synthetic sequencedescribed in example 111, due to hydrolysis of the cyano group. Thiscompound was purified via pH 2 preparative LC/MS (MeCN/water with TFA)to give the product as TFA salt. LCMS calculated for C₃₅H₃₇N₈O₄ (M+H)⁺:m/z=633.3; Found: 633.3.

Example 112.5-Acetyl-N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: Ethyl5-acetyl-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate

A mixture of ethyl5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (0.46g, 1.37 mmol) (from example 108, step 1), Palladium(II) acetate (7.7 mg,0.034 mmol) in 1-butyl-3-methylimidazolium tetrafluoroborate (2.81 mL,15.1 mmol) was vacuumed and backfilled with N₂ three times. To themixture was added 1-(vinyloxy)butane (0.90 mL, 6.84 mmol) and Et₃N (0.23mL, 1.64 mmol) and the reaction mixture was stirred at 115° C.overnight. The resulting mixture was then cooled to rt, treated with HClsolution (7.07 ml, 11.63 mmol), stirred at rt for 30 min, and extractedwith CH₂Cl₂. The combined organic layers were concentrated, and purifiedvia column chromatography (0% to 100% EtOAc in hexanes) to give theproduct (0.22 g, 54%). LCMS calcd for C₁₇H₁₈NO₄ (M+H)⁺: m/z=300.1.Found: 300.2.

Step 2:5-Acetyl-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic Acid

A mixture of ethyl5-acetyl-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate(0.070 g, 0.23 mmol) in 1 M NaOH solution (1.0 mL) and MeOH (2.0 mL) wasstirred at rt for 1 h, and then neutralized with 1 N HCl solution to pH5. The resulting solid was collected by filtration, and dried to givethe product (0.052 g, 82%). LCMS calcd for C₁₅H₁₄NO₄ (M+H)⁺: m/z=272.1.Found: 272.1.

Step 3:5-Acetyl-N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 83, step 5, using5-acetyl-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acidinstead of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. This compound was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₆H₃₈N₇O₄(M+H)⁺: m/z=632.3. Found: 632.4. ¹H NMR (500 MHz, DMSO) δ 11.67 (s, 1H),8.95 (s, 1H), 8.00 (s, 1H), 7.86-7.78 (m, 2H), 7.66-7.59 (m, 2H),7.59-7.53 (m, 1H), 7.50-7.37 (m, 4H), 6.67 (s, 1H), 4.57-4.51 (m, 1H),4.09-4.01 (m, 1H), 3.47-3.36 (m, 1H), 3.27-3.15 (m, 1H), 2.97-2.83 (m,1H), 2.73-2.66 (m, 1H), 2.63 (s, 3H), 2.31 (s, 3H), 2.09-1.96 (m, 2H),1.68-1.45 (m, 2H), 1.01 (t, J=6.8 Hz, 6H).

Example 113.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(5-fluoropyridin-3-yl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Step 1: Ethyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate

To a mixture of cyclohexane-1,3-dione (1.0 g, 8.9 mmol) in DMF (10 mL)was added 1 M t-BuOK in THF (8.9 mL, 8.9 mmol) at 0° C. The resultingmixture was stirred for 20 min and added ethyl(E)-2-cyano-3-ethoxyacrylate (1.51 g, 8.9 mmol). The reaction mixturewas warmed to rt, stirred for 2 h, quenched with IN HCl solution, andextracted with EtOAc. The combined organic layers were concentrated andpurified via column chromatography (0% to 100% EtOAc in hexanes) to givethe product. LCMS calcd for C₁₂H₁₃O₅ (M+H)⁺: m/z=237.1. Found: 237.2.

Step 2:1-(5-Fluoropyridin-3-yl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicAcid

A mixture of ethyl2,5-dioxo-5,6,7,8-tetrahydro-2n-chromene-3-carboxylate (0.28 g, 1.185mmol) and 5-fluoropyridin-3-amine (0.133 g, 1.19 mmol) in EtOH (3 mL)was stirred at rt overnight, treated with 1 M NaOH solution (2 mL),stirred at rt for 1 h, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product (0.065 g, 18%). LCMS calcd forC₁₅H₁₂FN₂O₄ (M+H)⁺: m/z=303.1. Found: 303.2.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(5-fluoropyridin-3-yl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 83, step 5, using1-(5-fluoropyridin-3-yl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid instead of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. This compound was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₆H₃₆FN₈O₄(M+H)⁺: m/z=663.3. Found: 663.4. ¹H NMR (600 MHz, DMSO) δ 11.38 (s, 1H),8.96 (s, 1H), 8.86 (d, J=2.6 Hz, 1H), 8.68-8.62 (m, 1H), 8.16-8.12 (m,1H), 8.09 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 6.75(s, 1H), 4.58-4.51 (m, 1H), 4.12-4.03 (m, 1H), 3.46-3.36 (m, 1H),3.26-3.16 (m, 1H), 2.94-2.85 (m, 1H), 2.75-2.63 (m, 1H), 2.63-2.52 (m,4H), 2.09-1.95 (m, 4H), 1.69-1.47 (m, 2H), 1.06-0.93 (m, 6H).

Example 114.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-7,7-dimethyl-2,5-dioxo-1-(pyridin-3-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Step 1: Ethyl7,7-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate

To a mixture of 5,5-dimethylcyclohexane-1,3-dione (2.0 g, 14.3 mmol) inDMF (20 mL) was added 1M t-BuOK in THF (14.3 mL, 14.3 mmol) at 0° C. Theresulting mixture was stirred for 20 min, added ethyl(E)-2-cyano-3-ethoxyacrylate (2.41 g, 14.3 mmol), warmed to rt, andstirred overnight. The reaction mixture was quenched with 1 N HClsolution, extracted with EtOAc, and the combined organic layers wereconcentrated and purified via column chromatography (0% to 100% EtOAc inhexanes) to give the product (2.8 g, 74%). LCMS calcd for C₁₄H₁₇O₅(M+H)⁺: m/z=265.1. Found: 265.2.

Step 2:7,7-Dimethyl-2,5-dioxo-1-(pyridin-3-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicAcid

A mixture of ethyl7,7-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate (244mg, 0.92 mmol) and pyridin-3-amine (87 mg, 0.92 mmol) in EtOH (3 mL) wasstirred at 60° C. overnight, cooled to rt, and the resulting solid wascollected by filtration, and dried to give the product (170 mg, 59%).LCMS calcd for C₁₇H₁₇N₂O₄ (M+H)⁺: m/z=313.1. Found: 313.2.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-7,7-dimethyl-2,5-dioxo-1-(pyridin-3-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 83, step 5, using7,7-dimethyl-2,5-dioxo-1-(pyridin-3-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid instead of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. This compound was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₈H₄₁N₈O₄(M+H)⁺: m/z=673.3. Found: 673.4. ¹H NMR (500 MHz, DMSO) δ 11.44 (s, 1H),8.95 (s, 1H), 8.80 (dd, J=4.8, 1.4 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.09(s, 1H), 8.01 (dt, J=8.1, 1.9 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.73 (dd,J=8.1, 4.8 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 6.76 (s, 1H), 4.59-4.49 (m,1H), 4.12-4.03 (m, 1H), 3.46-3.37 (m, 1H), 3.26-3.15 (m, 1H), 2.96-2.84(m, 1H), 2.74-2.65 (m, 1H), 2.49-2.42 (m, 4H), 2.11-1.96 (m, 2H),1.69-1.46 (m, 2H), 1.10-0.89 (m, 12H).

Example 115.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(5-fluoropyridin-3-yl)-6,6-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Step 1: Ethyl6,6-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate

To a mixture of 4,4-dimethylcyclohexane-1,3-dione (1.8 g, 12.8 mmol) inDMF (10 mL) was added 1 M t-BuOK in THF (12.8 mL, 12.8 mmol) at 0° C.The resulting mixture was stirred for 20 min, added ethyl(E)-2-cyano-3-ethoxyacrylate (2.17 g, 12.8 mmol), warmed to rt, andstirred overnight. The reaction mixture was quenched with 1 N HClsolution, extracted with EtOAc, and the combined organic layers wereconcentrated and purified via column chromatography (0% to 100% EtOAc inhexanes) to give the product (2.7 g, 80%). LCMS calcd for C₁₄H₁₇O₅(M+H)⁺: m/z=265.1. Found: 265.2.

Step 2:1-(5-Fluoropyridin-3-yl)-6,6-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicAcid

A mixture of ethyl6,6-dimethyl-2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate (200mg, 0.76 mmol) and 5-fluoropyridin-3-amine (85 mg, 0.76 mmol) in EtOH (3mL) was stirred at 60° C. overnight, cooled to rt, and purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product (75 mg,30%). LCMS calcd for C₁₇H₁₆FN₂O₄ (M+H)⁺: m/z=331.1. Found: 331.2.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-(5-fluoropyridin-3-yl)-6,6-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 83, step 5, using1-(5-fluoropyridin-3-yl)-6,6-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylicacid instead of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. This compound was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₈H₄₀FN₈O₄(M+H)⁺: m/z=691.3. Found: 691.4.

Example 116.N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-oxo-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxamide

Step 1: Sodium [imino(pyridin-3-yl)methyl](phenyl)azanide

Aniline (931 mg, 10.0 mmol) was added to 1.0 M sodiumhexamethyldisilazane in THF (10 mL, 10.0 mmol). The resulting mixturewas stirred at rt for 10 min, added 3-pyridinecarbonitrile (1.04 g, 10.0mmol), stirred at rt for 1 h, and concentrated. The residue was treatedwith ether, and the resulting solid was collected by filtration, washedwith ether and dried to afford the product (2.10 g, 100%), which wasused directly in the next step. LCMS calcd for C₁₂H₁₂N₃ (M+2H—Na)⁺:m/z=198.1. Found: 198.1.

Step 2: Ethyl6-oxo-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxylate

To a solution of sodium [imino(pyridin-3-yl)methyl](phenyl)azanide(0.219 g, 1.00 mmol) in MeCN (5 mL) was added ammonium chloride (0.054g, 1.00 mmol), followed by (ethoxymethylene)propanedioic acid, diethylester (0.20 mL, 1.00 mmol). The reaction mixture was stirred at 80° C.for 2 h, cooled to rt, and concentrated. The resulting residue wasdissolved in EtOAc, and washed with water and brine. The organic layerwas separated, dried over MgSO4, concentrated, and purified via columnchromatography (0% to 50% EtOAc in hexanes) to afford the product (0.167g, 52%). LCMS calcd for C₁₈H₁₆N₃O₃ (M+H)⁺: m/z=322.1. Found: 322.2.

Step 3: 6-Oxo-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxylicAcid

A mixture of ethyl6-oxo-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxylate (133mg, 0.41 mmol) and lithium iodide (138 mg, 1.03 mmol) in pyridine (2.5mL) was stirred at 115° C. overnight, cooled to rt, and concentrated.The resulting residue was dissolved in water (2 mL) and extracted withEtOAc (3 mL×2). The aqueous layer was slowly acidified to pH 4 with 1 NHCl solution, and extracted with 5% MeOH in CH₂Cl₂ (3 mL×3). Thecombined organic layers were washed with brine, dried over MgSO₄, andconcentrated to give the product (0.103 g, 85%), which was used directlyin the next step. LCMS calcd for C₁₆H₁₂N₃O₃ (M+H)⁺: m/z=294.1. Found:294.1.

Step 4:N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-oxo-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 83, step 5, using6-oxo-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxylic acidinstead of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. This compound was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₇H₃₆N903(M+H)⁺: m/z=654.3. Found: 654.3.

Example 117.N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-cyclopropyl-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxamide

Step 1. (2-Cyclopropyl-2-oxoethyl)(triphenyl)phosphonium Bromide

A solution of 2-bromo-1-cyclopropylethanone (2.44 g, 15.0 mmol) and PPh₃(3.93 g, 15.0 mmol) in THF (60 mL) was stirred at reflux for 1 h, andcooled to rt. The resulting solid was collected by filtration, andwashed with ether to afford the product (3.91 g, 61%), which was useddirectly in the next step. LCMS calcd for C₂₃H₂₂OP (M-Br)⁺: m/z=345.1.Found: 345.2.

Step 2: 1-Cyclopropyl-2-(triphenylphosphoranylidene)ethanone

A mixture of (2-Cyclopropyl-2-oxoethyl)(triphenyl)phosphonium bromide(3.91 g, from previous step) in IN NaOH solution (40 mL) was stirredovernight, and extracted with CH₂Cl₂. The combined organic layers werewashed with brine, dried over MgSO₄, and concentrated to afford theproduct (2.60 g, 50%). LCMS calcd for C₂₃H₂₂OP (M+H)⁺: m/z=345.1. Found:345.2.

Step 3: 6-Cyclopropyl-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxylicAcid

To a solution of 1-cyclopropyl-2-(triphenylphosphoranylidene)ethanone(1.72 g, 5.0 mmol) in THF (25 mL) was added diethyl 2-oxomalonate (1.3g, 7.5 mmol). The resulting mixture was stirred at rt for 30 min,concentrated, and the residue was added to phenylhydrazine hydrochloride(1.08 g, 7.50 mmol) in EtOH/H₂O (1:1, 50 mL). The reaction mixture wasstirred at 80° C. overnight. After cooling to rt, the organic solventswere evaporated, and the residue was diluted with CH₂Cl₂ (30 mL), andextracted with IN NaOH solution (5 mL×3). The combined aqueous layerswere adjusted with 6 N HCl to pH 4, and extracted with EtOAc (5 mL×3).The combined organic layers were washed with water and brine, dried overMgSO₄, and concentrated to give the product (0.562 g, 44%), which wasused directly in the next step. LCMS calcd for C₁₄H₁₃N₂O₃ (M+H)⁺:m/z=257.1. Found: 257.1.

Step 4:N-{4-[4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-6-cyclopropyl-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 83, step 5, using6-cyclopropyl-3-oxo-2-phenyl-2,3-dihydropyridazine-4-carboxylic acidinstead of1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid. This compound was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₅H₃₇N₈O₃(M+H)⁺: m/z=617.3. Found: 617.3.

Example 118.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide

Step 1: 5-Bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxylic Acid

A mixture of ethyl5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxylate (800 mg, 2.37mmol) (from Affinity Research Chemicals) in THF (7.9 mL)/MeOH (5.3mL)/water (2.6 mL) was treated with lithium hydroxide monohydrate (0.33mL, 11.9 mmol) at 0° C. The reaction mixture was stirred at rt for 60min, concentrated, and added water. The resulting mixture wasneutralized with 12 M HCl solution to pH 67, and the resulting solid wascollected by filtration, washed with water, and dried to give theproduct as a light yellow powder (784 mg, 100%). LCMS calcd forC₁₂H₁₀BrN₂O₃ (M+H)⁺: m/z=309.0. Found: 309.0.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2-bipyridine]-3-carboxamide

To a mixture of 5-bromo-6-methyl-2-oxo-2n-[1,2′-bipyridine]-3-carboxylicacid (9.0 mg, 0.03 mmol) and1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(10 mg, 0.03 mmol) (from example 83, step 2) in DMF (528 μl) was addedEt₃N (11 μl, 0.08 mmol), followed by HATU (20 mg, 0.053 mmol). Theresulting mixture was stirred at rt for 20 min, filtered, and the crudewas purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as TFA salt. LCMS calcd for C₃₃H₃₄BrN₈O₃ (M+H)⁺: m/z=669.2.Found: 669.2. ¹H NMR (500 MHz, DMSO) δ 11.69 (s, 1H), 8.75-8.67 (m, 2H),8.60 (s, 1H), 8.17 (td, J=7.8, 1.9 Hz, 1H), 8.05 (s, 1H), 7.81 (d, 7=8.7Hz, 1H), 7.73-7.62 (m, 3H), 7.46 (d, J=8.6 Hz, 1H), 6.72 (s, 1H), 4.55(d, J=13.6 Hz, 1H), 4.07 (d, J=12.2 Hz, 1H), 3.42 (s, 1H), 3.27-3.16 (m,1H), 2.91 (p, 7=6.7 Hz, 1H), 2.78-2.61 (m, 2H), 2.16 (s, 2H), 2.12-1.95(m, 2H), 1.58 (dd, J=59.5, 11.1 Hz, 2H), 1.02 (t, J=6.6 Hz, 6H).

Example 119.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-6-methyl-5-(oxazol-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide

Step 1: 1-Cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylicAcid

A microwave vial was charged with (FZ)-3-((dimethylamino)methylene)-6-methyl-2H-pyran-2,4(3H)-dione (1.92 g,7.95 mmol) (from example 97, step 1), cyclopropanamine (0.83 mL, 11.92mmol) and t-BuONa (1.13 g, 11.76 mmol) in EtOH (5.0 mL). The resultingmixture was stirred at 90° C. for 18 h, cooled to rt, concentrated, andpartitioned between water and CH₂Cl₂. The aqueous layer was acidifiedwith 4 N HCl solution and extracted with CH₂Cl₂. The combined organiclayers were washed with water, brine, dried over Na₂SO₄, andconcentrated to give the product (1.1 g, 42%). LCMS calcd for C₁₀H₁₂NO₃(M+H)⁺: m/z=194.1. Found: 194.1.

Step 2:5-Bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylicAcid

A suspension of1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (0.83g, 4.30 mmol) in glacial acetic acid (6.0 mL) was treated with Br₂ (0.29mL, 5.58 mmol) and the reaction mixture was stirred at rt for 4 days.Additional Br₂ (100 μL) was added and the reaction mixture was stirredovernight, diluted with water, and the resulting solid was collected byfiltration, washed with water, and dried to give the product as a beigesolid (1.0 g, 86%). LCMS calcd for C₁₀H₁₁BrNO₃ (M+H)⁺: m/z=272.0. Found:272.0.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide

A mixture of1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(278 mg, 0.74 mmol) (from example 83, step 2),5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylicacid (200 mg, 0.74 mmol), HATU (335 mg, 0.88 mmol) and Et₃N (0.21 mL,1.47 mmol) in DMF (5.0 mL) was stirred at rt for 2 h, and then directlypurified via column chromatography to afford the product (252 mg, 54%).LCMS calcd for C₃₁H35BrN₇O₃ (M+H)⁺: m/z=632.2. Found: 632.1.

Step 4:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-6-methyl-5-(oxazol-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxamide

To a solution ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide(20 mg, 0.032 mmol) and 2-(tributylstannyl)oxazole (11 mg, 0.032 mmol)in 1,4-dioxane (2.0 mL) was added Pd(Ph₃P)₄ (7.3 mg, 6.3 μmol). Thereaction mixture was stirred at reflux overnight, cooled to rt, and theresulting mixture was purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₄H₃₇N₈O₄(M+H)⁺: m/z=621.3. Found: 621.3.

Example 120.(S)—N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-(3-hydroxybut-1-yn-1-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A mixture of1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(257 mg, 0.68 mmol) (from example 83, step 2),5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (200 mg,0.68 mmol), HATU (310 mg, 0.82 mmol) and Et₃N (0.19 mL, 1.36 mmol) inDMF (5.0 mL) was stirred at rt for 2 h. The reaction mixture was thenpurified via column chromatography to afford the product (310 mg, 70%).LCMS calcd for C₃₃H₃₃BrN₇O₃ (M+H)⁺: m/z=654.2. Found: 654.3.

Step 2:(S)—N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-(3-hydroxybut-1-yn-1-yl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(20 mg, 0.031 mmol) was dissolved in MeCN (10 mL), followed by theaddition of (S)-but-3-yn-2-ol (4.7 mg, 0.067 mmol),tris(tert-butyl)phosphine (1.0 mL), Pd(Ph₃P)₄ (3.5 mg, 3.1 μmol),copper(I) iodide (0.36 mg, 1.9 μmol), and Et₃N (0.019 mL, 0.14 mmol).The resulting mixture was stirred at 70° C. for 16 h, cooled to rt, andpurified via pH 2 preparative LC/MS (MeCN/water with TFA) to give theproduct as TFA salt. LCMS calcd for C₃₇H₃₈N₇O₄ (M+H)⁺: m/z=644.3. Found:644.5.

Example 121.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5′-fluoro-5,6-dimethyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-5′-fluoro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide(8.0 mg, 0.012 mmol) (example 101, step 2) and PdCl₂(dppf)-CH₂Cl₂ adduct(1.0 mg, 1.2 μmol) in 1,4-dioxane (0.50 mL) was sealed in a microwavevial, evacuated and refilled with N₂ several times, followed by theaddition of 2.0 M dimethylzinc in toluene (0.023 mL, 0.047 mmol). Thereaction mixture was heated and stirred at 90° C. for 1 h, cooled to rt,and quenched with ice-water. The crude material was diluted with DMF andpurified via pH 10 preparative LC/MS (MeCN/water with NH₄OH) to give thedesired product as a white solid. LCMS calcd for C₃₄H₃₆FN₈O₃ (M+H)⁺:m/z=623.3. Found: 623.3.

Example 122.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-5-(cyanomethyl)-6-methyl-2-oxo-1-(pyridin-2-yl)-1,2-dihydropyridine-3-carboxamide

In a sealed tube a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide(10 mg, 0.02 mmol) (example 118, step 2), isoxazol-4-ylboronic acid (2.5mg, 0.02 mmol) in 1,4-dioxane (0.30 mL),N-ethyl-N-isopropylpropan-2-amine (7.7 μL, 0.05 mmol) and water (60 μL)was stirred together before Pd(tBu₃)₂ (3.8 mg, 7.5 μmol) was added. Thereaction mixture was sealed and then heated and stirred at 110° C. for 1h, cooled to rt, diluted with DMF, and purified via pH 10 preparativeLC/MS (MeCN/water with NH₄OH) to give the desired product as a whitesolid. LCMS calcd for C₃₅H₃₆N₉O₃ (M+H)⁺: m/z=630.3. Found: 630.3.

Example 123.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide

In a sealed tube a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide(8.0 mg, 0.012 mmol) (example 118, step 2),(1-methyl-1H-pyrazol-5-yl)boronic acid (2.3 mg, 0.02 mmol), and DIPEA(4.6 mg, 0.036 mmol) in 1,4-dioxane (200 μL) and water (40 μL) wasstirred together before Pd(tBu₃)₂ (3.1 mg, 6 μmol) was added. Thereaction mixture was sealed and then heated and stirred at 110° C. for50 min, cooled to rt, diluted with DMF, and purified via pH 10preparative LC/MS (MeCN/water with NH₄OH) to give the desired product asa white solid. LCMS calcd for C₃₇H₃₉N₁₀O₃ (M+H)⁺: m/z=671.3. Found:671.3. ¹H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 8.74 (dd, J=4.9, 1.1 Hz,1H), 8.38 (s, 1H), 8.18 (td, J=7.8, 1.9 Hz, 1H), 7.91 (s, 1H), 7.80 (d,J=8.6 Hz, 2H), 7.76 (d, J=ID Hz, 1H), 7.70-7.63 (m, 1H), 7.56 (d, J=1.8Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 6.58 (s, 1H), 6.42 (d, J=1.9 Hz, 1H),4.54 (d, J=11.9 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 1H), 3.40 (t, J=11.9 Hz,1H), 3.25-3.12 (m, 1H), 2.91 (p, J=6.8 Hz, 1H), 2.75-2.60 (m, 1H),2.16-1.97 (m, 1H), 1.87 (s, 3H), 1.81-1.73 (m, 1H), 1.51 (d, J=13.9 Hz,2H), 1.02 (t, J=6.6 Hz, 6H).

Example 124.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-chloro-6-methyl-2-oxo-2n-[1,2′-bipyridine]-3-carboxamide

To a microwave vial was addedN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide(8.0 mg, 0.01 mmol) (example 118, step 2) and nickel(II) chloride (1.4mg, 0.02 mmol) in DMF (0.40 mL). The vial was sealed and the reactionmixture was stirred at 180° C. under microwave conditions for 30 min,cooled to rt, and purified via pH 10 preparative LC/MS (MeCN/water withNH₄OH) to give the desired product as a white solid. LCMS calcd forC₃₃H₃₄ClN₈O₃ (M+H)⁺: m/z=625.2. Found: 625.2.

Example 125.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-2n-[1,2′-bipyridine]-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 123, using1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of (1-methyl-1 n-pyrazol-5-yl)boronic acid. This compound waspurified via pH 10 preparative LC/MS (MeCN/water with NH₄OH) to give thedesired product as a white solid. LCMS calcd for C₃₇H₃₉N₁₀O₃ (M+H)⁺:m/z=671.3. Found: 671.3.

Example 126.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(oxazol-2-yl)-2-oxo-2n-[1,2′-bipyridine]-3-carboxamide

To a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide(10 mg, 0.02 mmol) (example 118, step 2), and Pd(Ph₃P)₄ (3.5 mg, 3.0μmol) in toluene (0.30 mL) was added 2-(tributylstannyl)oxazole (10.7mg, 0.03 mmol). The reaction mixture was sealed in a microwave vial,vacuumed and backfilled with N₂ several times, and then heated andstirred at 120° C. for 22 h. The reaction mixture was cooled to rt,concentrated, and purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as TFA salt. LCMS calcd for C₃₆H₃₆N₉O₄ (M+H)⁺:m/z=658.3. Found: 658.3.

Example 127.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-(difluoromethyl)-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide

Step 1:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-5-vinyl-2H-[1,2-bipyridine]-3-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide(40 mg, 0.06 mmol) (example 118, step 2),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13.8 mg, 0.09 mmol),Na₂CO₃ (20.9 mg, 0.20 mmol), and[1,1′-Bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (4.5mg, 6.0 μmol) in tert-butyl alcohol (0.19 mL) and water (0.07 mL) wasdegassed with nitrogen, and then stirred and heated at 115° C. for 2 h.The resulting mixture was cooled to rt, diluted with EtOAc, washed withsaturated NaHCO₃ solution, water, and brine, dried over Na₂SO₄,concentrated, and purified via column chromatography (0 to 15% MeOH inEtOAc) to give the desired product as an off-white solid (27.9 mg, 76%).LCMS calcd for C₃₅H₃₇N₈O₃ (M+H)⁺: m/z=617.3. Found: 617.3.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-formyl-6-methyl-2-oxo-2H-[1,2-bipyridine]-3-carboxamide

To a solution ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-2-oxo-5-vinyl-2H-[1,2′-bipyridine]-3-carboxamide(20.0 mg, 0.032 mmol) in THF (0.37 mL) was added OsO₄ in water (4 wt. %)(0.06 mL, 9.7 μmol) and sodium periodate (32.6 mg, 0.15 mmol) in water(0.03 mL). The reaction mixture was stirred at 70° C. for 1 h, cooled tort, filtered through a plug of Celite, rinsed with THF, concentrated,and purified via pH 10 preparative LC/MS (MeCN/water with NH₄OH) to givethe desired product as a light yellow solid (6.5 mg, 31%). LCMS calcdfor C₃₄H₃₅N₈O₄ (M+H)⁺: m/z=619.3. Found: 619.3.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-(difluoromethyl)-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide

To a solution ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-formyl-6-methyl-2-oxo-2H-[1,2′-bipyridine]-3-carboxamide(8.0 mg, 0.01 mmol) in THF (0.16 mL) at 0° C. was slowly added(diethylamino)sulfur trifluoride (DAST) (0.034 mL, 0.259 mmol). Theresulting reaction mixture was warmed to rt and stirred at rt for 21 h,diluted with DMF, and purified via pH 2 preparative LC/MS (MeCN/waterwith TFA) to give the product as TFA salt. LCMS calcd for C₃₄H₃₅F₂N₈O₃(M+H)⁺: m/z=641.3. Found: 641.3.

Example 128.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamide

Step 1: Methyl5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate

A mixture of methyl 5-bromo-4-oxo-1,4-dihydropyridine-3-carboxylate (151mg, 0.65 mmol) and Cs₂CO₃ (420 mg, 1.3 mmol) in DMF (3 mL) was stirredat rt for 15 min and then isopropyl iodide (0.16 mL, 1.6 mmol) wasadded. The reaction mixture was stirred at rt for 11 days, diluted withEtOAc, filtered through Celite concentrated, and purified via columnchromatography (0% to 100% EtOAc in hexanes then 0% to 10% methanol inCH₂Cl₂) to give the product as an off-white solid (103 mg, 58%). LCMScalcd for C₁₀H₁₃BrNO₃ (M+H)⁺: m/z=274.0. Found: 274.1.

Step 2: 5-Bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic Acid

To a solution of methyl5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylate (103 mg,0.376 mmol) in MeOH (2 mL) was added 3 M NaOH (0.2 mL) and the reactionmixture was stirred at rt for 4 h, acidified with 1 N HCl, diluted withbrine, and extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, and concentrated to afford the crude product as anoff-white solid, which was used directly in the next step (97 mg, 99%).LCMS calcd for C₉H₁₁BrNO₃ (M+H)⁺: m/z=260.0. Found: 260.0.

Step 3: tert-Butyl4-(4-amino-5-(4-(5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

A solution of 5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylicacid (83 mg, 0.319 mmol) and HATU (146 mg, 0.383 mmol) in DMF (2 mL) wastreated with DIPEA (0.11 mL, 0.638 mmol). This mixture was then addedvia a cannula to a solution of tert-butyl4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(130 mg, 0.319 mmol) (example 107, step 4) in DMF (1 mL). The reactionmixture was stirred at rt for 40 min, diluted with water and extractedtwice with EtOAc. The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated, and purified via column chromatography(0% to 100% EtOAc in hexanes then 0% to 10% MeOH in CH₂Cl₂) to give theproduct as a yellow solid (208 mg, 100%). LCMS calcd for C₃₁H₃₇BrN₇O₄(M+H)⁺: m/z=650.2. Found: 650.2.

Step 4: tert-Butyl4-(4-amino-5-(4-(1-isopropyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(4-amino-5-(4-(5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(76 mg, 0.117 mmol), pyridin-3-ylboronic acid (17.2 mg, 0.140 mmol),XPhos-Pd-G2 (9.2 mg, 0.012 mmol) and potassium phosphate tribasic (62mg, 0.292 mmol), in 1,4-dioxane/water (5:1, 2.4 mL) was degassed withnitrogen, and then heated and stirred at 90° C. for 2 h. The reactionmixture was cooled to rt, diluted with EtOAc, dried over Na₂SO₄,filtered through Celite, concentrated, and purified via columnchromatography (0% to 100% EtOAc in hexanes then 0% to 10% MeOH inCH₂Cl₂) to give the product as an off-white solid (60 mg, 79%). LCMScalcd for C₃₆H₄₁N₈O₄ (M+H)⁺: m/z=649.3. Found: 649.3.

Step 5:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamide

A suspension of tert-butyl4-(4-amino-5-(4-(l-isopropyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(60 mg, 0.092 mmol) in CH₂Cl₂ (1 mL) was treated with 4 M HCl in1,4-dioxane (1 mL). The reaction mixture was stirred at rt for 2 h, andconcentrated to afford a light yellow solid which was directly used inthe next step. LCMS calcd for C₃₁H₃₃N₈O₂ (M+H)⁺: m/z=549.3. Found:549.3.

Step 6:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamide

A mixture ofN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamide(20 mg, 0.036 mmol) and Et₃N (0.030 ml, 0.215 mmol) in CH₂Cl₂ (1 mL) wastreated dropwise with 60 μL of a 10% (v/v) solution of isobutyrylchloride in CH₂Cl₂. The reaction mixture was stirred at rt for 40 min,quenched with saturated NaHCO₃ solution, and extracted three times withEtOAc. The combined organic layers were dried over Na₂SO₄, concentrated,and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to affordthe product as an off-white solid (15 mg as TFA salt). LCMS calcd forC₃₅H₃₉N₈O₃ (M+H)⁺: m/z=619.3. Found: 619.3.

Example 129.N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-5-(5-fluoropyridin-3-yl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 128, using3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine insteadof pyridin-3-ylboronic acid in step 4. This compound was purified via pH2 preparative LC/MS (MeCN/water with TFA) to give the product as the TFAsalt. LCMS calcd for C₃₅H₃₈FN₈O₃ (M+H)⁺: m/z=637.3. Found: 637.3.

Example 130.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

Step 1: 5-Bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxylic Acid

A mixture of ethyl5-bromo-6-methyl-2-oxo-2n-[1,3′-bipyridine]-3-carboxylate (570 mg, 1.69mmol) (from Affinity Research Chemicals) and LiOH monohydrate (355 mg,8.45 mmol) in MeOH (12 mL) and water (2.0 mL) was stirred at rt for 2 h,and MeOH was evaporated. To the residue was added water and theresulting mixture was made slightly acidic by addition of 1 N HCl, whichcaused a solid to form. The solids were collected by filtration, washedwith water, and dried to give the product as a pink solid (333 mg, 64%).LCMS calcd for C₁₂H₁₀BrN₂O₃ (M+H)⁺: m/z=309.0. Found: 309.0.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

To a mixture of1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(150 mg, 0.396 mmol) (Example 83, step 2) and5-bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxylic acid (123 mg,0.396 mmol) in DMF (3.0 mL) was added Et₃N (0.083 mL, 0.594 mmol),followed by HATU (181 mg, 0.476 mmol). The resulting mixture was stirredat rt for 3 h, added water, and stirred for another 15 min. Theresulting solid was collected by filtration, washed with water, anddried to give the product (250 mg, 94%). A portion of this material wasfurther purified via pH 2 preparative LC/MS (MeCN/water with TFA) togive the product as TFA salt. LCMS calcd for C₃₃H₃₄BrN₈O₃ (M+H)⁺:m/z=669.2. Found: 669.2. ¹H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 8.75(dd, J=4.8, 1.5 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.58 (s, 1H), 8.09 (s,1H), 7.97 (ddd, J=8.1, 2.4, 1.6 Hz, 1H), 7.81 (d, J=8.7 Hz, 2H), 7.68(dd, J=7.9, 4.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 6.75 (s, 1H), 4.53 (d,J=12.8 Hz, 1H), 4.06 (d, J=13.3 Hz, 1H), 3.49-3.32 (m, 1H), 3.19 (t,J=11.8 Hz, 1H), 2.98-2.79 (m, 1H), 2.68 (t, J=11.5 Hz, 1H), 2.19 (s,3H), 2.11-1.93 (m, 2H), 1.56 (dd, J=59.6, 10.9 Hz, 2H), 1.00 (t, J=6.8Hz, 6H).

Example 131.N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-chloro-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide(30 mg, 0.045 mmol) (Example 130, step 2) and copper(I) chloride (13.3mg, 0.134 mmol) in DMF (0.5 mL) was heated and stirred at 170° C. undermicrowave conditions for 12 min. The reaction mixture was cooled to rt,filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA)to give the product as TFA salt. LCMS calcd for C₃₃H₃₄ClN₈O₃ (M+H)⁺:m/z=625.2. Found: 625.3. ¹H NMR (600 MHz, DMSO) δ 11.73 (s, 1H), 8.76(s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.12 (s, 1H), 7.98 (ddd, J=8.1,2.4, 1.5 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.69 (dd, J=8.0, 4.8 Hz, 1H),7.47 (d, J=8.6 Hz, 2H), 6.77 (s, 1H), 4.53 (d, J=11.8 Hz, 1H), 4.06 (d,J=12.9 Hz, 1H), 3.41 (tt, J=11.8, 3.5 Hz, 1H), 3.20 (t, J=12.7 Hz, 1H),2.89 (hept, J=6.8 Hz, 1H), 2.68 (t, J=11.9 Hz, 1H), 2.16 (s, 3H), 2.01(dd, J=29.4, 12.3 Hz, 2H), 1.57 (dd, J=73.5, 9.4 Hz, 2H), 1.01 (d, J=6.9Hz, 6H).

Example 132.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5,6-dimethyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

To a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide(30 mg, 0.045 mmol) (Example 130, step 2) and PdCl₂(dppf)-CH₂Cl₂ adduct(0.9 mg, 1.1 μmol) in 1,4-dioxane (0.50 mL) was added 2.0 M dimethylzinc in toluene (0.086 mL, 0.172 mmol) dropwise under an atmosphere ofN₂. The resulting mixture was stirred at 90° C. overnight, cooled to rt,filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA)to give the product as TFA salt. LCMS calcd for (M+H)⁺: m/z=605.3.Found: 605.3.

Example 133.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

In a sealed vial, a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-methyl-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide(20 mg, 0.030 mmol) (Example 130, step 2),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(12.4 mg, 0.060 mmol), XPhos Pd G2 (2.4 mg, 3.0 μmol) and potassiumphosphate tribasic (19.0 mg, 0.090 mmol) in 1,4-dioxane (0.40 mL)/water(0.07 mL) was stirred at 90° C. under N₂ overnight. The reaction mixturewas then cooled to rt, filtered, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₇H₃₉N₁₀O₃ (M+H)⁺: m/z=671.3. Found: 671.4.

Example 134.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 133, using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.This compound was purified via pH 2 preparative LC/MS (MeCN/water withTFA) to give the product as TFA salt. LCMS calcd for C₃₇H₃₉N₁₀O₃ (M+H)⁺:m/z=671.3. Found: 671.4.

Example 135.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-6-methyl-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-2H-[1,3′-bipyridine]-3-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 133, using1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 n-pyrazoleinstead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1n-pyrazole. This compound was purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₇H₃₉N₁₀O₃ (M+H)⁺: m/z=671.3. Found: 671.4.

Example 136.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1: Ethyl5-bromo-6-(bromomethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate

To a mixture of ethyl5-bromo-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (310mg, 0.92 mmol) (from Affinity Research Chemicals) and NBS (197 mg, 1.11mmol) in carbon tetrachloride (6.0 mL)/chloroform (2.5 mL) was added2,2′-Azo-bis-isobutyronitrile (15.1 mg, 0.092 mmol). The resultingmixture was stirred at reflux for 6 h, cooled to rt, and concentrated.The resulting material was purified via column chromatography (20% to70% EtOAc in hexanes) to give the product as a yellow solid (234 mg,61%). LCMS calcd for C₁₅H₁₄Br₂NO₃ (M+H)⁺: m/z=413.9. Found: 414.0.

Step 2:5-Bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylicAcid

A mixture of ethyl5-bromo-6-(bromomethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate(100 mg, 0.24 mmol) and LiOH monohydrate (50.5 mg, 1.21 mmol) in MeOH (4mL) and water (0.7 mL) was stirred at rt for 1 h, and MeOH wasevaporated. To the residue was added water and the resulting mixture wasmade slightly acidic by addition of 1 N HCl, which caused a solid toform. The solids were collected by filtration, washed with water, anddried to give the product as a yellow solid (79 mg, 97%). LCMS calcd forC₁₄H₁₃BrNO₄ (M+H)⁺: m/z=338.0. Found: 338.0.

Step 3: tert-Butyl4-(4-amino-5-(4-(5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenyl)pyrrolo[1,2-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(95.0 mg, 0.23 mmol) (Example 107, step 4),5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylicacid (79 mg, 0.23 mmol), and Et₃N (0.049 mL, 0.349 mmol) in DMF (1.2 mL)was added HATU (106 mg, 0.28 mmol). The resulting mixture was stirred atrt for 2 h, added water, and stirred for another 10 min. The resultingsolid was collected by filtration, washed with water, and dried to givethe product as a light yellow solid (156 mg, 92%). LCMS calcd forC₃₆H₃₉BrN₇O₅ (M+H)⁺: m/z=728.2. Found: 728.4.

Step 4:N-(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamideDihydrochloride

To a solution of tert-butyl4-(4-amino-5-(4-(5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(54 mg, 0.074 mmol) in CH₂Cl₂ (400 μL) was added 4 N HCl in 1,4-dioxane(148 μL, 0.59 mmol). The resulting mixture was stirred at rt for 2 h,concentrated, and dried to give the product, which was used directly inthe next step (50 mg, 96%). LCMS calcd for C₃₁H₃₁BrN₇O₃ (M+H)⁺:m/z=628.2. Found: 628.3.

Step 5:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a mixture ofN-(4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-(methoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamidedihydrochloride (20.0 mg, 0.029 mmol) and Et₃N (0.020 mL, 0.14 mmol) inCH₂Cl₂ (0.40 mL) was added isobutyryl chloride (3.1 μL, 0.030 mmol). Theresulting mixture was stirred at rt overnight, concentrated, andpurified via pH 2 preparative LC/MS (MeCN/water with TFA) to give theproduct as TFA salt. LCMS calcd for C₃₅H₃₇BrN₇O₄ (M+H)⁺: m/z=698.2.Found: 698.2. ¹H NMR (500 MHz, DMSO) δ 11.82 (s, 1H), 8.58 (s, 1H), 8.03(s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.63-7.53 (m, 3H), 7.45 (d, J=8.6 Hz,2H), 7.40 (d, J=6.8 Hz, 2H), 6.69 (s, 1H), 4.53 (d, J=12.7 Hz, 1H), 4.14(s, 2H), 4.05 (d, J=13.8 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 3.18 (d,J=12.9 Hz, 1H), 2.99 (s, 3H), 2.94-2.81 (m, 1H), 2.68 (t, J=12.7 Hz,1H), 2.10-1.95 (m, 2H), 1.56 (dd, J=60.6, 9.7 Hz, 2H), 1.01 (d, J=6.6Hz, 6H).

Example 137.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-cyano-6-(ethoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

Step 1:5-Bromo-6-(ethoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylicAcid

A mixture of ethyl5-bromo-6-(bromomethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate(40 mg, 0.10 mmol) (Example 136, step 1) and LiOH monohydrate (22 mg,0.52 mmol) in EtOH (1.2 mL) and water (0.2 mL) was stirred at rt for 2h, and EtOH was evaporated. To the residue was added water and theresulting mixture was made slightly acidic by addition of 1 N HCl, whichcaused a solid to form. The solid was collected by filtration, washedwith water, and dried to give the product as a yellow solid (25 mg,69%). LCMS calcd for C₁₅H₁₅BrNO₄ (M+H)⁺: m/z=352.0. Found: 352.0.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-(ethoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

To a mixture of1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(26 mg, 0.069 mmol) (Example 83, step 2) and5-bromo-6-(ethoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylicacid (24 mg, 0.069 mmol) in DMF (0.40 mL) was added Et₃N (0.014 mL, 0.10mmol), followed by HATU (31 mg, 0.082 mmol). The resulting mixture wasstirred at rt for 90 min, added water, and stirred for another 10 min.The resulting solid was collected by filtration, washed with water, anddried to give the product as a light yellow solid (47 mg, 96%). LCMScalcd for C₃₆H₃₉BrN₇O₄ (M+H)⁺: m/z=712.2. Found: 712.2.

Step 3:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-cyano-6-(ethoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-6-(ethoxymethyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide(18.0 mg, 0.025 mmol), Pd(OAc)₂ (0.23 mg, 1.0 μmol), XantPhos (1.2 mg,2.02 μmol), Zinc cyanide (3.0 mg, 0.025 mmol) and TMEDA (1.1 μL, 7.6μmol) in DMF (0.50 mL) was degassed with N₂, and then heated and stirredat 160° C. for 10 min under microwave conditions. The reaction mixturewas cooled to rt, filtered, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₇H₃₉N₈O₄ (M+H)⁺: m/z=659.3. Found: 659.3. ¹H NMR (500 MHz, DMSO) δ11.40 (s, 1H), 8.65 (s, 1H), 8.01 (s, 1H), 7.81 (d, J=8.6 Hz, 2H),7.68-7.52 (m, 3H), 7.50-7.38 (m, 4H), 6.67 (s, 1H), 4.51 (s, 1H), 4.22(s, 2H), 4.04 (s, 1H), 3.40 (t, J=11.7 Hz, 1H), 3.31-3.12 (m, 3H),2.95-2.82 (m, 1H), 2.65 (d, J=26.7 Hz, 1H), 2.12-1.94 (m, 2H), 1.76-1.38(m, 2H), 1.13-0.88 (m, 9H).

Example 138.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-3-(1,4-dimethyl-1H-pyrazol-3-yl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 1,4-dimethyl-1H-pyrazol-3-amine instead of1-methyl-1H-pyrazol-4-amine. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₄H₄₁N₁₀O₄ (M+H)⁺: m/z=653.3. Found: 653.5.

Example 139.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

Step 1: Diethyl 2-((cyclopropylamino)methylene)malonate

To a solution of diethyl 2-(ethoxymethylene)malonate (2.16 g, 10.0 mmol)in MeCN (20 mL) was added cyclopropylamine (0.70 mL, 10.1 mmol). Thereaction mixture was stirred at rt overnight, then at 80° C. for 1 h,cooled to rt, and concentrated to give the crude product, which was useddirectly in the next step. LCMS calcd for C₁₁H₁₈NO₄ (M+H)⁺: m/z=228.1.Found: 228.1.

Step 2: Ethyl1-cyclopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of diethyl 2-((cyclopropylamino)methylene)malonate (0.45 g,2.00 mmol) and isocyanatobenzene (0.476 g, 4.00 mmol) in pyridine (0.97mL) was heated and stirred at 170° C. for 3 h, cooled to rt, andpurified via column chromatography (0% to 10% MeOH in CH₂Cl₂) to givethe product (0.336 g, 56%). LCMS calcd for C₁₆H₁₇N₂O₄ (M+H)⁺: m/z=301.1.Found: 301.2.

Step 3:1-Cyclopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicAcid

A mixture of ethyl1-cyclopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate(0.336 g, 1.12 mmol) in 4.0 M HCl in 1,4-dioxane (2.24 mL, 8.95 mmol)and water (0.56 mL) was stirred at 80° C. for 3 h, cooled to rt, andconcentrated to afford the crude product, which was used directly in thenext step. LCMS calcd for C₁₄H₁₃N₂O₄ (M+H)⁺: m/z=273.1. Found: 273.1.

Step 4:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide

To a mixture of1-cyclopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL)was added1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(0.019 g, 0.050 mmol) (Example 83, step 2) and Et₃N (0.021 mL, 0.150mmol). The reaction mixture was stirred at rt for 2 h, diluted withMeOH, adjusted with TFA to pH 2, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₅H₃₇N₈O₄ (M+H)⁺: m/z=633.3. Found: 633.3.

Example 140.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-2,4-dioxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 139, using 3-isocyanatopyridine instead ofisocyanatobenzene in step 2. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₄H₃₆N₉O₄ (M+H)⁺: m/z=634.3. Found: 634.3.

Example 141.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1′-cyclopropyl-2′-methyl-4′-oxo-1′,4′-dihydro-[2,3′-bipyridine]-5′-carboxamide

Step 1: 3-((Dimethylamino)methylene)-6-methyl-2H-pyran-2,4(3H)-dione

To a solution of 6-methyl-2H-pyran-2,4(3H)-dione (11.5 g, 91 mmol) intoluene (30 mL) was added N,N-dimethylformamide dimethyl acetal (13.1mL, 98 mmol). The reaction mixture was then stirred overnight, andconcentrated to give the crude product, which was used directly in thenext step. LCMS calcd for C₉H₁₂NO₃ (M+H)⁺: m/z=182.1. Found: 182.3.

Step 2: 1-Cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylicAcid

A mixture of3-((dimethylamino)methylene)-6-methyl-2H-pyran-2,4(3H)-dione (1.92 g,7.95 mmol), cyclopropanamine (0.83 mL, 11.9 mmol) and sodiumtert-butoxide (1.13 g, 11.8 mmol) in EtOH (5.0 mL) was heated andstirred at 90° C. for 18 h, cooled to rt, concentrated, and treated withwater and CH₂Cl₂. The aqueous solution was acidified with 4 N HCl andextracted with CH₂Cl₂. The combined organic layers were washed withwater, brine, dried over Na₂SO₄, and concentrated to give the desiredcompound (1.1 g, 42%). LCMS calcd for C₁₀H₁₂NO₃ (M+H)⁺: m/z=194.1.Found: 194.3.

Step 3:5-Bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylicAcid

A suspension of1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (0.83g, 4.30 mmol) in glacial acetic acid (6.0 mL) was treated with Br₂ (0.29mL, 5.58 mmol). The reaction mixture was stirred at rt for 4 days, addedadditional Br₂ (100 μL), and stirred overnight. The reaction mixture wasdiluted with water, and the resulting solid was collected by filtration,washed with water, and dried to give the product as a beige solid (1.0g, 86% yield). LCMS calcd for C₁₀H₁₁BrNO₃ (M+H)⁺: m/z=272.0. Found:272.2.

Step 4:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide

A mixture of1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(278 mg, 0.735 mmol) (Example 83, step 2),5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylicacid (200 mg, 0.735 mmol), HATU (335 mg, 0.882 mmol) and Et₃N (0.21 mL,1.47 mmol) in DMF (5.0 mL) was stirred at rt for 2 h, and then purifiedvia column chromatography to give the product (252 mg, 54%). LCMS calcdfor C₃₁H₃₅BrN₇O₃ (M+H)⁺: m/z=632.2. Found: 632.3.

Step 5:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1′-cyclopropyl-2′-methyl-4′-oxo-1′,4′-dihydro-[2,3′-bipyridine]-5′-carboxamide

To a solution ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide(20.0 mg, 0.032 mmol) and 2-(tributylstannyl)pyridine (11.3 mg, 0.032mmol) in 1,4-dioxane (2.0 mL) was added Pd(Ph₃P)₄ (7.3 mg, 6.3 μmol).The reaction mixture was heated and stirred at reflux overnight, cooledto rt, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) togive the product as TFA salt. LCMS calcd for C₃₆H₃₉N₈O₃ (M+H)⁺:m/z=631.3. Found: 631.1. ¹H NMR (500 MHz, DMSO) δ 13.0-11.8 (m, 1H);8.95 (m, 1H); 8.71 (s, 1H); 8.45 (m, 1H); 8.25 (s, 1H); 7.95-7.80 (m,4H); 7.50 (m, 2H); 6.85 (m, 1H); 4.60 (m, 1H); 4.10 (m, 1H); 3.81 (m,1H); 3.41 (m, 1H); 3.25 (m, 1H); 2.85 (m, 1H); 2.65 (m, 1H); 2.41 (s,3H); 2.1-1.9 (m, 2H); 1.7-1.4 (m, 2H); 1.3-1.1 (m, 4H); 1.0 (m, 6H).

Example 142.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-2,2′-dimethyl-4-oxo-1,4-dihydro-[3,3′-bipyridine]-5-carboxamide

To a solution of (2-methylpyridin-3-yl)boronic acid (4.3 mg, 0.032 mmol)andN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide(20.0 mg, 0.032 mmol) (Example 141, step 4) in 1,4-dioxane (2.0 mL) andwater (0.2 mL) were added K₂CO₃ (26.0 mg, 0.188 mmol) and Pd(Ph₃P)₄(10.1 mg, 8.7 μmol). The reaction mixture was heated at reflux andstirred for 12 h, cooled to rt, and purified via pH 2 preparative LC/MS(MeCN/water with TFA) to give the product as TFA salt. LCMS calcd forC₃₇H₄₁N₈O₃ (M+H)⁺: m/z=645.3. Found: 645.1.

Example 143.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyrimidin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using pyrimidin-2-amine instead of 1-methyl-1n-pyrazol-4-amine in step 1. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₃H₃₇N₁₀O₄ (M+H)⁺: m/z=637.3. Found: 637.3. ¹H NMR (400MHz, DMSO) δ 10.68 (s, 1H), 9.08 (d, J=4.9 Hz, 2H), 8.73 (s, 1H), 8.08(s, 1H), 7.84-7.72 (m, 3H), 7.46 (d, J=8.6 Hz, 2H), 6.75 (s, 1H), 4.76(p, J=6.7 Hz, 1H), 4.59-4.49 (m, 1H), 4.12-4.01 (m, 1H), 3.49-3.34 (m,1H), 3.27-3.14 (m, 1H), 2.90 (p, J=6.7 Hz, 1H), 2.76-2.61 (m, 1H),2.11-1.94 (m, 2H), 1.72-1.49 (m, 2H), 1.45 (d, J=6.8 Hz, 6H), 1.01 (s,6H).

Example 144.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 139, using 2-isocyanatopyridine instead ofisocyanatobenzene in step 2. This compound was purified via pH 2preparative LC/MS (MeCN/water with TFA) to give the product as TFA salt.LCMS calcd for C₃₄H₃₆N₉O₄ (M+H)⁺: m/z=634.3. Found: 634.3. ¹H NMR (600MHz, DMSO) δ 10.81 (s, 1H), 8.64 (ddd, J=4.9, 1.9, 0.8 Hz, 1H), 8.53 (s,1H), 8.13-8.00 (m, 2H), 7.83-7.74 (m, 2H), 7.56 (ddd, J=7.5, 4.9, 1.0Hz, 1H), 7.52 (dt, J=8.0, 0.9 Hz, 1H), 7.49-7.41 (m, 2H), 6.73 (s, 1H),4.54 (d, J=12.2 Hz, 1H), 4.07 (d, J=12.8 Hz, 1H), 3.41 (tt, J=11.8, 3.6Hz, 1H), 3.34-3.28 (m, 1H), 3.20 (t, J=12.3 Hz, 1H), 2.90 (p, J=6.7 Hz,1H), 2.69 (t, J=12.0 Hz, 1H), 2.02 (dd, J=30.8, 12.2 Hz, 2H), 1.67-1.47(m, 2H), 1.17-0.84 (m, 10H).

Example 145.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(5-fluoropyridin-2-yl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 5-fluoropyridin-2-amine instead of1-methyl-1H-pyrazol-4-amine in step 1. This compound was purified via pH2 preparative LC/MS (MeCN/water with TFA) to give the product as TFAsalt. LCMS calcd for C₃₄H₃₇FN₉O₄ (M+H)⁺: m/z=654.3. Found: 654.3.

Example 146.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-oxo-5-(pyridin-2-yl)-1,4-dihydropyridine-3-carboxamide

Step 1:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide

To a mixture of1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one(200 mg, 0.53 mmol) (example 83, step 2) and5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (137 mg,0.53 mmol) (example 128, step 2) in DMF (4.0 mL) was added Et₃N (0.11mL, 0.79 mmol), followed by HATU (241 mg, 0.63 mmol). The resultingmixture was stirred at rt for 3 h, added water, and stirred for another15 min. The resulting solid was collected by filtration, washed withwater, and dried to give the product. LCMS calcd for C₃₀H₃₅BrN₇O₃(M+H)⁺: m/z=620.2. Found: 620.2.

Step 2:N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-oxo-5-(pyridin-2-yl)-1,4-dihydropyridine-3-carboxamide

To a mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide(40.0 mg, 0.064 mmol), Pd(PPh₃)₄ (14.9 mg, 0.013 mmol) in toluene (1.2mL) was added 2-(tributylstannyl)pyridine (0.042 mL, 0.129 mmol). Themixture was purged with N₂, and heated and stirred at 120° C. overnight.The reaction mixture was then cooled to rt, diluted with MeOH, filteredand purified via pH 2 preparative LC/MS (MeCN/water with TFA) to givethe product as TFA salt. LCMS calcd for C₃₅H₃₉N₈O₃ (M+H)⁺: m/z=619.3.Found: 619.3.

Example 147.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-cyclopropyl-6-methyl-4-oxo-5-(pyridin-3-yl)-1,4-dihydropyridine-3-carboxamide

A mixture ofN-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide(12.0 mg, 0.019 mmol) (example 141 step 4), pyridin-3-ylboronic acid(2.8 mg, 0.023 mmol),Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Xphos Pd G2) (1.5 mg, 1.90 μmol), and potassium phosphatetribasic (8.9 mg, 0.042 mmol) in 1,4-dioxane (0.50 mL) and water (0.10mL) were degassed with N₂, and then heated and stirred at 80° C. for 2h. The reaction mixture was then cooled to rt, diluted with MeOH,filtered, and purified via pH 2 preparative LC/MS (MeCN/water with TFA)to give the product as TFA salt. LCMS calcd for C₃₆H₃₉N₈O₃ (M+H)⁺:m/z=631.3. Found: 631.3.

Example 148.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-3-(1,5-dimethyl-1H-pyrazol-3-yl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 1,5-dimethyl-1H-pyrazol-3-amine instead of1-methyl-1H-pyrazol-4-amine in step 1. This compound was purified via pH2 preparative LC/MS (MeCN/water with TFA) to give the product as TFAsalt. LCMS calcd for C₃₄H₄₁N₁₀O₄ (M+H)⁺: m/z=653.3. Found: 653.3.

Example 149.N-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-3-(6-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

This compound was prepared following a synthetic sequence analogous tothat for example 87, using 6-methylpyridin-2-amine instead of1-methyl-1H-pyrazol-4-amine in step 1. This compound was purified via pH2 preparative LC/MS (MeCN/water with TFA) to give the product as TFAsalt. LCMS calcd for C₃₅H₄₀N₉O₄ (M+H)⁺: m/z=650.3. Found: 650.3.

Example A

Axl Autophosphorylation Assay

Autophosphorylation of Axl was carried out by incubating the recombinantAxl protein (Life Technologies, PV4275) in buffer containing 50 mM Tris,pH7.5, 0.2 mg/ml Axl, 5 mM ATP, 20 mM MgCl₂ and 2 mM DTT at roomtemperature for 1 hour.

TAM Enzymatic Assay

The kinase assay buffer contained 50 mM HEPES, pH7.5, 10 mM MgCl2, 1 mMEGTA, 0.01% NP-40 and 2 mM DTT. 0.1 ul test compounds dissolved in DMSOwere transferred from compound plates to white 384-well assay plates(Greiner LLIMITRAC plates). The final concentration of DMSO was 1.25%.Enzyme solutions of 5.1 nM phosphor-Axl, or 0.0625 nM c-Mer (CarnaBiosciences, 08-108), or 0.366 nM Tyro3 (Life Technologies, PR7480A)were prepared in assay buffer. A 1 mM stock solution of peptidesubstrate Biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO: 1 (Quality ControlledBiochemicals, MA) dissolved in DMSO was diluted to 1 uM in assay buffercontaining 2000 uM ATP. 4 ul enzyme solution (or assay buffer for theenzyme blank) was added to the appropriate wells in each plate, and then4 ul/well substrate solution was added to initiate the reaction. Theplate was protected from light and incubated at room temperature for 60min. The reaction was stopped by adding 4 ul detection solutioncontaining 50 mM Tris-HCl, pH7.8, 150 mM NaCl, 0.05% BSA, 45 mM EDTA,180 nM SA-APC (Perkin Elmer, CR130-100) and 3 nM Eu-W1024anti-phosphotyrosine PY20 (Perkin Elmer, AD0067). The plate wasincubated for 1 h at room temperature, and HTRF (homogenous timeresolved fluorescence) signal was measured on a PHERAstar FS platereader (BMG labtech). Percentage of inhibition was calculated for eachconcentration and IC50 value was generated from curve fitting withGraphPad Prism software.

The compounds provided herein were found to be inhibitors of TAMaccording to the TAM Enzymatic Assay. All the compounds as describedherein have been tested. The compounds shown in Table 1 below exhibit anIC₅₀ of less than 1 μM against at least one kinase selected from Tyro3,Axl and Mer.

The compounds provided herein were found to be inhibitors of one or moreof AXL, MER, and TYRO3. IC₅₀ data is provided below in Table 1. Thesymbol “†” indicates an IC₅₀ of ≤5 nM, “††” indicates an IC₅₀ of >5 nMbut ≤10 nM. “†††” indicates an IC₅₀ of >10 nM but ≤100 nM; “†††”indicates an IC₅₀ of greater than 100 nM; and na indicates notavailable.

TABLE 1 Axl Mer Tyro3 IC₅₀ IC₅₀ IC₅₀ Example (nM) (nM) (nM)  1 ††† †††††††  2 ††† ††† ††††  3 †††† †††† ††††  4 †††† †††† ††††  5 †††† †††††††† 7 (cis †† † †††† isomer) 7 (trans † † ††† isomer)  8 ††† ††† †††† 9 ††† ††† ††† 10 ††† ††† †††† 11 ††† †† †††† 12 ††† † †††† 13 †† †††††† 14 † † ††† 15 † † ††† 16 † † ††† 17 † † ††† 18 † † †† 19 † † † 20††† †† †††† 21 †† † ††† 22 † † ††† 23 † † ††† 24 † † ††† 25 † † ††† 26 †† ††† 27 † † ††† 28 † † †††† 29 † † ††† 30 † † ††† 31 † † ††† 32 † † †††33 † † ††† 34 † † ††† 35 † † †† 36 †† †† †††† 37 † † ††† 38 † † ††† 39 †† ††† 40 †† †† †††† 41 † † ††† 42 † † ††† 43 † † ††† 44 † † †††† 45 † †††† 46 † † ††† 47 † † ††† 48 †† †† ††† 49 † † ††† 50 † † ††† 51 † † ††52 † † ††† 53 †† † ††† 54 † † ††† 55 † † †† 56 †† †† †††† 57 † †† ††††58 † †† †††† 59 † ††† †††† 60 † †† ††† 61 † † ††† 62 † † ††† 63 † † †††64 † † ††† 65 † † ††† 66 † †† ††† 67 † † †††† 68 † † †††† 69 † †† ††††70 † † ††† 71 † †† ††† 72 † †† †††† 73 † †† †††† 74 † † ††† 75 † † †††76 † †† †††† 77 † ††† †††† 78 † † ††† 79 † † ††† 80 † †† †††† 81 † † †††82 † † ††† 83 † † ††† 84 †† ††† †††† 85 † ††† †††† 86 ††† ††† †††† 87 †† †††† 88 † † ††† 89 na na na 90 †† ††† †††† 91 † ††† †††† 92 na na na93 † † † 94 † †† †††† 95 † ††† †††† 96 † † ††† 97 † †† ††† 98 † † ††† 99† † ††† 100  ††† ††† †††† 101  † † †††† 102  † † ††† 103  † † ††† 104  †† †† 105  † †† ††† 106  † † †††† 107  † †† †††† 108  † † ††† 109  † † ††110  † †† †††† 111  † † †††† 111a †† ††† †††† 112  † † ††† 113  † † †††114  † † ††† 115  † ††† †††† 116  † † ††† 117  † †† †††† 118  † † ††††119  † † †††† 120  † † †††† 121  † † †††† 122  † † †††† 123  † †† ††††124  † †† †††† 125  † † †††† 126  † † †††† 127  † † †††† 128  † †† ††††129  † †† †††† 130  † † †††† 131  † † †††† 132  † † †††† 133  † †† ††††134  † †† †††† 135  † † †††† 136  † † †††† 137  † †† †††† 138  † †† ††††139  † † †††† 140  † †† †††† 141  † † †††† 142  † †† †††† 143  † †† ††††144  † †† †††† 145  na na na 146  na na na 147  † † †††† 148  † †† ††††149  † †† ††††

Example B. Generation of BAF3-AXL, BAF3-MER and BAF3-TYRO3 Cells andCell Proliferation Assay

The cytoplasmic domain of AXL, MER, or TYRO3 fused with dimerizationsequence and HA tag was cloned into pMSCV vector withpuromycin-resistance marker to generate three constructs (pMSCV-AXL,pMSCV-MER and pMSCV-TYRO3). BAF3 cells were transfected with the threeconstructs individually by electroporation. Single clones that were IL3independent and puromycin-resistant were selected and characterized.Cells with stable expression of AXL, MER, or TYRO3 were selected anddesignated BAF3-AXL, BAF3-MER and BAF3-TYRO3 cells.

BAF3, BAF3-AXL, BAF3-MER or BAF3-TYRO3 cells lines were maintained inRPMI1640 with 10% FBS (Gibco/Life Technologies, Carlsbad, Calif.). Tomeasure the effect of test compounds on cell viability, 1000 cells/wellwere plated into 384 well tissue culture plates in growth medium with aserial dilution of compound or DMSO alone for 48 hours at 37° C. with 5%CO₂, cell viability was measured by ATP assay (CellTiter-Glo Assay,Promega) according to the manufacturer's procedure. The data wereconverted to percent inhibition relative to DMSO control and IC₅₀ curveswere fitted using GraphPad Prism software.

Example C. BaF3-AXL ELISA and BaF3-MER ELISA

BaF3-AXL or BaF3-MER cells were maintained in culture medium RPMI with10% FBS and puromycin (1 μg/ml, Gibco/Life Technologies, Carlsbad,Calif.). To measure the effect of test compounds on phosphor-AXL orphosphor-MER, the cells were plated (5×10⁴ cells/well) in a V-bottompolypropylene plate (Greiner bio-one) in the presence or absence of testcompounds diluted in culture medium, and incubated for 1 hour at 37° C.with 5% CO₂. The cells were harvested by centrifugation, and lysed in110 μl of ice cold lysis buffer (Cell Signaling) with protease andphosphatase inhibitors (Halts PI, Thermo Fisher) for 30 min on ice. Thecell lysate was stored at −80° C. for ELISA. ELISA plates were preparedby incubating Costar plate with anti-HA antibody (1 μg/ml) for 1 hour atroom temperature. The plates were washed and blocked with PBS with 3%BSA. Cell lysate were loaded onto ELISA plate and incubated at 4° C.overnight. The plates were washed and incubated with LANCE Eu-W1024anti-phospho-tyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assaybuffer (Perkin Elmer) for 1 hour, and read on the Pherastar (BMGLabtech). The data was converted to percent inhibition relative to DMSOcontrol and IC₅₀ determination was performed by fitting the curve ofpercent inhibition versus the log of the inhibitor concentration usingGraphPad Prism.

Example D. H1299 Phospho-AXL ELISA

H1299 cells (ATCC), human non-small cell lung carcinoma cell line withAxl expression, are maintained in culture medium RPMI with 10% FBS(Gibco/Life Technologies, Carlsbad, Calif.). To measure the effect oftest compounds on phosphor-AXL, the cells were plated (30000 cells/well)in 96 well tissue culture plates (Costar) and incubated overnight at 37°C. with 5% CO₂. Compounds at an appropriate concentration were added andincubated for 1 hour at 37° C. with 5% CO₂. rhGas6 (R&D Systems, 6μg/ml) were added to each well. Plates were incubated at 37° C. with 5%CO₂ for 15 min. Cells were harvested and lysed in 110 μL of ice coldlysis buffer (Cell Signaling) with protease and phosphatase inhibitors(Halts PI, Thermo Fisher). The lysate was incubated for 1 hour on iceand stored at −80° C. for ELISA. ELISA plates were prepared byincubating Costar plate with anti-HA antibody (1 μg/ml) for 1 hour atroom temperature. The plates were washed and blocked with PBS with 3%BSA. Cell lysate was loaded onto ELISA plates and incubated at 4° C.overnight. The plates were washed and incubated with LANCE Eu-W1024anti-phospho-tyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assaybuffer (Perkin Elmer) for 1 hour, and read on the Pherastar (BMGLabtech). The data was converted to percent inhibition relative to DMSOcontrol and IC₅₀ determination was performed by fitting the curve ofpercent inhibition versus the log of the inhibitor concentration usingGraphPad Prism.

Example E. Whole Blood H1299 Phospho-AXL ELISA

H1299 Cells (ATCC) are maintained in culture medium RPMI with 10% FBS(Gibco/Life Technologies, Carlsbad, Calif.). To measure the effect oftest compounds on phospho-AXL in whole blood, the cells are plated(30000 cells/well) in 96 well tissue culture plates (Costar) andincubated overnight at 37° C. with 5% CO₂. Blood obtained from normaldonors was mixed test compounds for 1 hour. Culture medium was removedfrom H1299 cells, and blood with compound was added to each well. After1 hour incubation at 37° C. with 5% CO₂, rh-Gas6 (4 μg/ml, R&D Systems)was added to each well. The plate was incubated at 37° C. with 5% CO₂for 15 min. The cells were washed with PBS, and lysed in 110 uL of icecold lysis buffer (Cell Signaling) with protease and phosphataseinhibitors (Halts PI, Thermo Fisher) for 1 hour on ice. The plate wasstored at −80° C. for ELISA. ELISA plates were prepared by incubatingCostar plate with anti-HA antibody (1 ug/ml) for 1 hour at roomtemperature. The plates were washed and blocked with PBS with 3% BSA.Cell lysate were loaded onto ELISA plate and incubated at 4° C.overnight. The plates were washed and incubated with LANCE Eu-W1024anti-phospho-tyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assaybuffer (Perkin Elmer) for 1 hour, and read on the Pherastar (BMGLabtech). The data was converted to percent inhibition relative to DMSOcontrol and IC₅₀ determination was performed by fitting the curve ofpercent inhibition versus the log of the inhibitor concentration usingGraphPad Prism.

Example F. G361 Phospho-Akt Cell Insight ELISA

G361 cells (ATCC), human malignant melanoma cell line expressing Mer,are maintained in culture medium RPMI with 10% FBS (Gibco/LifeTechnologies, Carlsbad, Calif.). To measure the effect of test compoundson MER signaling pathway, the cells were plated at 2×10⁴ cells/well in100 μL volume in 96 well CellBind surface plates (Corning), andincubated overnight at 37° C. with 5% CO₂. 20 μL of test compounds atappropriate concentrations were added to the cells and incubated for 1hour. rhGas6 (4 μg/ml, R&D Systems) was added to each well, andincubated for 20 min. The cells were fixed by adding 50 uL 4%paraformaldehyde (Electron Microscopy Sciences) in PBS (Corning) for 30min at room temperature. Plates were washed and incubated with 50 uL0.2% triton X-100 (Sigma) in PBS for 10 minutes at room temperature.Plates were washed and incubated with 100 uL blocking buffer (0.1% BSAin PBS) for 30 min. Plates are washed and incubated with Phospho-AKT(Ser473) (D9E) rabbit mAb (Cell Signaling) diluted in 0.1% BSA (1:300dilution) at 4° C. overnight. Plates were washed and incubated with 50uL Alexaflour 488 F(ab′)² fragment of goat anti-rabbit IgG (H+L)(Molecular Probes, 1:1000 dilution) and Hoechst 33342 (Thermo Fisher,1:2000 dilution) in PBS at room temperature for 2 hours. Plates werewashed with PBS, and read on Cell Insight CX5 (Thermo Fisher).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A method for treating a cancer in a patient, saidmethod comprising: administering to the patient a therapeuticallyeffective amount of a compound which isN-(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-dioxo-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide,or a pharmaceutically acceptable salt thereof, wherein the cancer is asarcoma.
 2. The method of claim 1, wherein the sarcoma is selected fromrhabdosarcoma, Kaposi sarcoma, and osteosarcoma.
 3. The method of claim1, wherein the sarcoma is selected from chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.
 4. The method of claim 1, wherein the sarcoma isleiomyosarcoma.